I've tried playing Arkham Horror with 1, 2 and 4 players. I've found that the game seems extraordinarily difficult with less than 4 characters. Simply put, you don't have enough gos to do everything. Gates keep opening, monsters keep appearing, and it only takes 1 curse, a bad monster, or a couple of delayed turns and it's all over. Adding any expansions simply kicks the difficulty up further.
After several frustrating games, I now don't play with less than 4 characters. In a two player game, each of us takes two characters, and plays the game as if there were 4 players. This seems to give a better balance, but is a lot to remember and keep track of.
Has anyone had success playing Arkham with less than 4 characters? In particular, have you managed a reasonable game with two players and two characters (i.e., one character each)? How did you manage it? Did you have to adjust any of the rules?