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For me, the clear answer is Castlevania: Lords of Shadow. I've started the game no fewer than 4 different times since I bought it, but I just haven't been able to get through it. This, despite the fact I loved Castlevania IV, Castlevania: Dracula X, and several of the more recent ones.
In my most recent playthrough, it was the little grenades that those goblin-things throw that finally convinced me to stop trying. I couldn't even see them on the screen before they blew up in my face.
I have tried over and over again to get into it since it came out (I actually went to the midnight release) and I never could. It just bores the hell out of me. The only things that I ever enjoyed were the free-roam multiplayer and undead overrun.