Fallout 3: The constant micromanaging of weapons, ammo, radiation, karma, money, skills, etc etc coupled with sketchy AI and horrible world geometry pushed me away from what in my opinion could have been an exceptionally great game.
Halo 3 Multiplayer: Inability to customize matches and so-so maps keep that on the shelf except in cases of truly great self-inebriation.
CoD4/WAW Multiplayer: I'm not a fan of rewarding players for doing well within matches so that they can extend their leads on other players, as well as giving them better equipment for playing excessively.
Mass Effect: Good game, bad timing. A lot of other stuff that provided quicker satisfaction were available and I just would never get around to delving into it like I would KOTOR.
An older one:
Prince of Persia: The Warrior Within: I never realized how much I enjoyed the tone and stylings of Sands until I booted up Warrior. The extremely dark graphic style, goofy combat mechanics, and darker tone of the Prince turned me off after about 3 days. When the Prince called that woman a "*****" in the first fight, it just hit me in a way that made me thought, "Wow, this just does not seem right." It probably also didn't help that the copy I got was a worn out GC disc that required numerous wiping during gameplay, which kept taking me out of the action.