I would say Edward Scissorhands, though it’s hard to classify that as purely a comedy (in fact, almost every video store I’ve been to–even from one Blockbuster location to the next–has it shelved under a different category: comedy, drama, fantasy, science fiction… SCIENCE FICTION???). Much of the movie IS very humorous, and it’s extremely quirky.
But, in the case that you don’t think of it as a comedy/quirky score, then I’ll go with Nightmare Before Christmas. (Those are my two all-time favorite Elfman scores anyway… real original of me, huh?)