Racing games are usually an interest killer for me, mostly because my experiences with them can be summed up as such: The AI is either completely and utterly useless, or cheats like a ************.
RTS games do this too. Mostly because I'm awful at them and am rarely able to get passed even the earliest levels in the single player campaign (if there even is one).
Lastly, balance issues will kill my interest in the game, Two Worlds 2 being the most recent offender. I understand the logic of "magic is best, it's magic", I do, but when you apply it to a game, ISSUES OCCUR. There needs to be a viable reason to play as each type of class (warrior, rogue, etc.), with each class having a definite strength/weakness over the other classes. The mage being squishy doesn't count as a weakness anymore! Not when the mage can make a spell that gives him over 100% physical resistance! Or a spell that lets him summon a small army of undead knights that are three times his level and have a strength boost of 100%! It's one thing to have magic be powerful, it's another thing to literally be able to cast a spell, set down the controller, get up to make yourself a drink, and come back to find that you've won the boss fight!