New Vegas with one life, and extremely lethal bullet damage for enemies (1 shot is all it takes from the big ones). No DR.
Skyrim with no potions, sneaking, reloading, armor rating and most of the toughest mods there are.
Baldur's Gate 2 with ALL the unfair and/or "meant for normal difficulty" mods played on Insanity, no reloads, no level 9 spells in SoA, no HLA's at all, one dice roll for character attributes, rest of the party made by other players and thus having no influence on who do you get, no cheesy items or tactics. Complete ban on things like "protection from evil" and "protection from magic". Rest only after boss fights.
Dead Space 2 on zealot in one sitting, no reloads or checkpoints, blind.
Dark Messiah Hardcore with one life.
Rome Total War... Play as the worst (unplayable) faction (vanilla or modded) that has not a single top tier unit, don't attack major factions until they pour endless stacks your way, give Roman and other Major Power cities enough pop and process_cq them for total development and 24000 pop in the first few years. No trading. War with everyone.
There was more to Rome, but it's a blur now.
Warhammer Online (Now dead) Use one hand to beat an enemy.
These would be the more memorable ones i've done/am doing.