Considering it was because of my friends on teh intarw3bz that I started reading Terry Pratchett in the first place, I'd be interested in knowing the answers to this question.
I've been re-reading through a core selection of my favorites over the past week or so; Hogfather, Thud!, Witches Abroad, and now Reaper Man. When I finish Reaper Man, it's probably time for trip #3 through Night Watch.
It's hard to pick a favorite from that list, but his best stuff (to me anyway) shares a common property, in that you'll be reading a typical light, humorous Pratchett novel up until the last twenty-five or thirty pages, and then the continental shelf drops off under your feet and you find yourself in unexpectedly deep waters. Hogfather may have been the best at that:
"The sun would have risen just the same, yes?"...but I'm not sure. Picking a winner would be tough. I'd like to see your choices...
"Oh, come on. You can't expect me to believe that. It's an astronomical fact."
THE SUN WOULD NOT HAVE RISEN.
"Really? Then what would have happened, pray?"
A MERE BALL OF FLAMING GAS WOULD HAVE ILLUMINATED THE WORLD.