Well, putting aside that my imagination is a horrible, horrible place to be stuck in...there are some things.
.hack//INFECTION = So, you beat the nigh-unbeatable killing machine that is Skeith, whom has been one-hitting you and your comrades despite being levels above the dungeon limit, and he melts. Fabulous. Then, earthquakes start as the game (The World) you're playing in the game freaks out and something erupts from the ground... WHAT THE FUCK IS THAT?! [https://www.youtube.com/watch?v=_ew2L-AT9S8] No preparation, no explanation (yet), and actually no battle because this freaky-ass thing blasts you away by roaring. This is, of course, the setup to the rest of the series, but for a moment there I thought I had to fight that thing, and for the rest of the series I dreaded running into Cubia...
Extermination - So, this game was a Survival Horror game that was not a part of the Resident Evil franchise, which took things a different way. Your 'villain' was whatever the hell was growing and infecting everything in an Antarctic research center, and one of the things going on was that people - INCLUDING YOU - were being taken over when the infection reached a critical mass and exploded out through all your cells at once from a core area. There were alien organism inhabiting and taking over the human or animal body, but it wasn't just that. The alien infection spread everywhere. Walls, ceilings, floors... People were somehow trapped IN the walls suddenly, meaning that the stuff on the walls reached out and absorbed them, meaning that THE WALLS ARE EATING PEOPLE!!!
And of course...DEATHCLAWS!!! AAAAAAAAAAAAAAAAAAAAAAAAUUUUGGGGGGHHHHHHHH!!!!!!!!!