For the sake of the thread, let's define "non-traditional" as follows:

No Superheroes
Completely outside of the Adventure, Science-Fiction, Supernatural, Fantasy genres.
Acceptable genres: Humor, Romance, Non-Fiction, Dramatic, Mystery, among others.

For me, it's gotta be McCloud's Understanding Comics: The Invisible Art, followed closely by Peter Bagge's Hate (most recently collected in Buddy Does Seattle and Buddy Does Jersey).

Lill' Pureheart Powerful Archie.

Criminal series by Ed Brubaker and Sean Phillips.

100 Bullets would fit the category, I think.

Cerebus. I've never had a comic make me literally laugh out loud, the first half of the series is hilariously brilliant.

Easily From Hell for me, unless the short supernaturally-tinged scenes disqualify it..

...And the second half irrevocably ruined the whole thing for me.

For me, it's probably Strangers In Paradise. I heart Francine Peters.

It's non-traditional enough for me. I anticipated it getting mentioned at least once. Curious how many posts in we'll get 'til someone mentions Sandman or Death by Gaiman.

I think this thread may wind up expanding my AmazIMWAN wish list.

From Hell is my pick for the best-written comic ever published.

Too many to pick a favorite. Usagi Yojimbo? Cerebus? Mage: The Hero Discovered (though technically that could be fantasy, but then so many of these could be)? Sam And Max, Freelance Police? Stig's Inferno? Hate? Love & Rockets? Omaha The Cat Dancer? Would Elfquest be disqualified?

I can't pick. Sorry.

I liked Ms. Tree.

The first couple of Sin City stories were a hoot.

Box Office Poison
Ghost World
David Boring
Prison Funnies

Okay, I've decided.

Uncle Scrooge.

"Peanuts". I know it was a daily strip, but it's still comics!

I would say "Uncle Scrooge" too, but even though it's about funny animals it is essentially an adventure series.

Calvin & Hobbes.

Preacher! Of course you can't get much more supernatural than that, but it's still very much non-traditional!

My wife liked Ms. Tree. Also, Nathaniel Dusk was good.

Yeah, I would list this too, but I don't really consider it that non-traditional. Sure, it's not superheroes in tights, but it is Pulp Adventure with anti-heroes and heroes doing some pretty super things.

The Goon is really good. But it's about the supernatural as well as pulp fiction.

Box Office Poison, seconded. SO good.