At first I was annoyed that Mitch was the villain, but they ended up developing it really well - they did a really good job making me hate him (and Cartman). I found myself getting actually angry at the character (not the game) during the Community Center fight. The constant cheating was driving me nuts, and the taunting of "Yeah, that was stupid so it didn't count," or "Oh yeah, you're also on fire." was a beautiful touch. It was also the only time in the game I lost a fight more than once; after the third try, I had to revert to the previous checkpoint and buy a handful of healing products before going back in.
I actually really enjoyed the Shub-Niggurath fight, thought it was clever in both humor and execution. The Mutant Kyle fight didn't really hold the same appeal to me, although the foreshadowing throughout the game of Kyle showing up, doing something completely ineffective, and leaving, was a nice touch.
I also loved "Car!" at random intervals in the middle of street fights. If they'd done it all the time, it would have been annoying, but I only saw it 3-4 times in the game.