I and others have already mentioned this, but here it is again:
Permanent death. I'm talking about non story deaths, mainly in the Fire Emblem franchise. This also applies to the zombification in Ogre Battle 64. It's lame, cheap, and subjectively realistic. It is somehow realistic to have death be permanent but not allow you to do things differently during a stage to avoid it (like fighting an entire battle differently than the story would allow). It's like having free will with only bad choices. Definitely a poison pill for me.
The other issue for me often involves time limits. These can often ruin a game. The campaign missions in certain Starcraft stages and, apparently, all the stages in the sequel are a turn off. Occasionally, time limits can be okay, but using them everywhere just becomes an annoyance that can prevent me from enjoying the game as a whole.