That One Disadvantage

The disadvantage that no smart Minmaxer would ever take because it practically ensures a quick death or severe disruption of your plans.

Clear requirement: it should be presented as a disadvantage from the beginning. It should not just be a less smart option, it should clearly be labeled as an intentional handicap. You should get something in return for it. It has to be voluntarily chosen. And it has to be a completely disastrous option that is just plain not worth it.

Opposite of Minmaxer's Delight.

Role Playing Game

 * Completely Inept and Cursed At Birth in Avernum. Put them together for additional fun.
 * Exile 3 had the Pacifist disadvantage. While it was technically possible to give this to a magic user and still have a semi-viable party member, in a game that is basically a series of Dungeon Crawls, a pacifist is of limited utility.
 * Actually being a Pacifist made you able to take other nice benefits and retain a reasonable XP progression. This was the result of trade-offs: you advance slower or faster depending on your mix of edges and flaws. And it was certainly possible to keep one spellcaster busy doing nothing but healing and buffing, especially since buffs in Exile stack.
 * The Lord birthsign in Morrowind gave your character a semi-decent healing spell in return for turning him or her into kindling (100% weakness to fire). Enjoy Vampirism (50% weakness to fire).
 * On top of that, the healing spell is immediately made useless by the infinitely superior 'Hearth Heal' spell that can be bought by almost any NPC that sells Restoration spells. The Lord's healing spell heals 2HP per second for 30 seconds while Hearth Heal heals 20-80HP immediately, making it quicker and able to heal more HP overall. Characters who major in Restoration even start with this spell, making The Lord birthsign even more useless.
 * God help you if you're also a High Elf. (50% weakness to fire, so a Vampire High Elf under The Lord has 200% weakness to fire. Ouch.)
 * While The Atronach -- double magicka in exchange for no magicka regain from resting -- is played up to be this in-game, it's more annoying than deadly if one has decent knowledge of the game (i.e., potions that restore magicka better than resting are light weight, and free at any mage guild if you are a member, and that The Atronach also absorbs the blessings at altars for free restores.) It works out as an Elite Tweak in the end.
 * Actually, The Atronach is more of a Cursed With Awesome tweak: on top of double magicka, you get 50% spell absorption, allowing you to restore your magic by absorbing enemy spells, which also negates the damage. Assuming you get your hands on enchantments to cover the remaining 50% (which isn't hard; the Necromancer's Amulet, for example, is 25% by itself), you don't need to rest to recover magic, and you're immune to enemy spellcasters to boot.
 * The Apprentice birthsign in Oblivion is even worse than the Lord; you get 100 more magicka, but at the price of a 100% weakness to magic. If you're also a High Elf, then fire, frost, and shock damage spells are dealing 125% more damage to you.
 * One background option in Arcanum is "Nietzsche Poster Child", boosting EXP in exchange for increasing critical failure rate ("That which does not kill me can only make me stronger."). Given Arcanum has really annoying effects possible for critical failures (most are "deal damage to self", but also found are "receive injury that reduces stats and can only be healed by upper end healing items" and "your weapon breaks instantly", "Armor damaged", "get stunned and most likely die because the thing you were fighting now has a few turns of uninterrupted, unmissable attacks", and multiple of the above) and EXP is given like candy already, only a pure diplomat (who doesn't really make any rolls that can critically fail, plu s doesn't get the game's insane amount of combat EXP) can make any use of it, and even then, a background that boosts your persuasion stats (and the cap for them, as a stat's cap is based on its starting value) with a hit to combat stats may be better.
 * The version of the "Skilled Trait" in Fallout, Fallout 2, and Fallout Tactics is this. It makes you wait one extra level to gain a Perk, per Perk (you get them every 4, instead of every 3). In exchange, you get +5 skill points per level. The problem is, Perks are incredibly useful, and if you have a decent Intelligence (which you should, since Intelligence also determines your dialogue options), you'll be swimming in skill points by level 12 or so. For a comparison, the "Gifted" Trait grants +1 to each primary stat at a penalty of -10 to every skill and 5 fewer skill points per level, and is considered the best Trait in the game, bar none.

Simulation Game

 * The Moronic trait in Tropico is not a good trait to have, as it bars you from getting colleges.

Tabletop Games
"Like Unluckiness, but worse. Whenever anything goes wrong for your party, it happens to you, first and worst. If something goes right, it misses you. And any time the GM feels like hosing you, he can, and you have no gripe coming, because you are cursed."
 * GURPS has Combat Paralysis and high-value (e.g. -40+ for a whole government) Enemies. Both of them, however, pale in comparison to the Hemophila disadvantage, which makes ANY wound you suffer into either a royal pain in the ass, a life-threatening disaster, or a quick trip to the morgue.
 * There's actually a whole bunch in GURPS; woe on anyone who takes the disadvantages Cursed or Unluckiness - you're just begging the GM to be a dick towards you at the worst possible time. Here's the actual description for Cursed:


 * While the 75 free points you get for it are a massive advantage, especially for a low-level character, there's no way any GM worth the name isn't going to take a huge amount of pleasure in making you regret it. One of the jokes in the GURPS magazine, Pyramid, revolved around a disadvantage called Spontaneous Human Combustion -- also probably a bad one to take.
 * Klutz and Total Klutz likewise encourage the GM to screw with you in their description. "The GM should be creative in inventing minor torments."
 * There is an Easy to Kill disadvantage. I repeat, there is an Easy to Kill disadvantage. While it can be offset with plenty of Hp, DR, etc., it's rarely taken because it's only worth -2 points per level.
 * Unique sounds cool until you find out it means that if anything ever changes the time line significantly (and you can only take it in worlds where this is possible), you not only cease to exist, you cease to have ever existed, anywhere, with no chance of ever being remembered. You can also take it in parallel universe settings, where it's closer to Minmaxers Delight - not only do you get disadvantage points for taking it, it gives you the Zeroed advantage (i.e. your character is not listed in any of the usual publicly-available records) for free.
 * Slave Mentality requires you to make a rather difficult roll "before you can take any action that isn't either obeying a direct order or part of an established routine." And to do anything other than fold to social influence requires GM permission and another difficult roll. As the book says, "rarely appropriate for PCs"!
 * Also, maximum point value enemies are really fun.
 * At the highest level of Terminally Ill, your character will suddenly drop dead after a year or so; however, since that's its only effect, it can still be a Minmaxers Delight if you don't expect the campaign to last that long, though that's quite a real gamble if your GM hasn't let you know anything that could be used to gauge that at character creation.
 * Reduced Time Rate makes it so a character takes twice as long to perform any non-combat tasks, and in combat you declare all your actions (like punching that guy in front of you), then wait a turn, then perform those actions (like punching the air where that guy was last round).
 * Dark Fate in Legend of the Five Rings. Sure, it can save your bacon, but when the GM feels like it, you will betray everything your character holds dear, probably including the other players. Death is usually the result, although a Fate Worse Than Death is also a distinct possibility.
 * L5R is rife with these. Momoku, which removes the ability to spend void, is not even close to worth the 10 Character Points you get. The creators have noted that disadvantages in their system are supposed to be deadly, not a minor handicap, and taking one is supposed to be handing the GM an excuse to ruin you.
 * Dark Fate in the Old World of Darkness games. The books try to make it sound appealing by pointing out your Dark Fate means you have an effectively open hand until it hits (unless it's your Dark Fate, what can the situation do to you?), but realistically, the Storyteller will hammer you with your Dark Fate as soon as you screw up one too many of his plans.
 * Similarly, Life Saver in more than one of the Old World of Darkness games, with the wrong group. Because isn't everyone a Sociopathic Hero who is alright with butchering people?
 * Bleeder in Serenity is like GURPS Hemophilia - any significant wound is death. "Things Don't Go Smooth" is another bad one (the GM can void any success he likes once or twice per game session, typically the "do or die" ones) - notable in that Mal has it.
 * Although this shouldn't be too much of a surprise, considering it's named after one of his lines.
 * The highest level of Coward in All Flesh Must Be Eaten. Buy it and your character will never play any real role in the game ever again.
 * Dragon Magazine #325 has the Superstitious flaw. If you create a character with a crippling phobia of magic, maybe adventuring just isn't for you.
 * Another issue of Dragon includes a selection of extremely crippling commoner-oriented flaws, up to and including Corpse. Oddly enough, creative interpretation of several of these ended up being a significant boon and turned what was originally a class with no abilities and bare minimum stats into a Lethal Joke Character.
 * Dark Heresy has the Nascent Psyker background package. Notable in that it is the only background package that costs 0xp (the game lacking a point-buy advantage/disadvantage system), Nascent Psyker gives your character spectacular powers (fuelled by Hell) which they can't control, and which have a definite chance of randomly making you, or everyone around you explode, or sharing your head with a daemon. Oh, and you have to be under extreme stress before those powers will manifest, and if any other characters find out you have them, they are legally obliged to either kill you, or capture you and send you across the galaxy to learn how to control it over the next decade or so (both options effectively requiring you to retire the character). Even if you manage to hide it from the others (not particularly easy), or they are heretical/radical enough not to have you purged or sanctioned, it's only a matter of time before your magical mishaps kill you or worse... It is explicitly noted in the Splatbook it appears in that taking this package is effectively an open-ended death sentence.
 * In a time travel-themed RPG, you'd better take the advantage to be conscious of shifts in the timeline. Otherwise, your character will spend forever trying to figure out what you already know!
 * Dependence is this in the Hero System. While it was originally intended to replicate characters like Aquaman, who needed to dunk himself in water once a day, it turns into a bludgeon against the character, because all the GM has to do to screw over the guy is not allow access, storywise.
 * "Palms Like Sieves" in Hackmaster. And Hemophilia, again.
 * The Bloodfeeder for the Chaos Lord in Warhammer 40k. When used in melee, you roll 2 six-sided dice and get that many plus 4 attacks in that round (keep in mind that, for a character, you should usually get about five attacks). That is, unless you roll a 1 on either die, in which your Chaos Lord goes into a wrist-slitting emo mode, represented by him taking an armor-ignoring wound and forfeiting all of his attacks that round, which more-often-than-not coincides with him getting obliterated in whatever melee he was a part of. No surprise, the fluff clearly points out in many places that "Khorne cares not from whence the blood flows". The Chaos Marines have a number of Confusion Fu options in their codex, but the Bloodfeeder is by far the most self-destructive.
 * Anything with the Rage special rule must move directly towards the closest enemy as fast as possible. A unit is usually subject to Rage because of a bad roll on a certain test, or as a mechanical counterbalance to some other amazing ability (often Furious Charge or something of the like). Often the trademark of a particularly Ax Crazy model / unit. While it's a rather negligible drawback against new and inexperienced players, who will almost instinctively park on objectives and never move, a veteran player with a fast vehicle or two can drag Rage units by the nose all over the table.