Familiarity with comics and characters will add a level of mirth to the proceedings, but it's certainly not a prerequisite -- I didn't know until reading solicits well after the fact that Superduper was a take on the Legion of Super-Heroes, for example (mainly because Superduper has about fifty fewer members and they seem to have abandoned the "from the far future" angle). I'd say the real dealbreaker is going to be the violence or gore or language or...simply the unrepentant filth that permeates the soul not only of most of the characters but of everything that seems to happen to them. It's as rough as I've seen in any comic -- except maybe one (but more on that later).

Me, I gave up on Preacher twice (and eventually came back each time, and am glad I did so), and it was an ABC Family series compared to this. Ennis is often labeled as simply heartless and puerile, and I disagree -- it's just that it's often hard to see the emotional core under all the misery and grime he slogs upon it.

But here's one of my favorite sequences in it -- occurs about midway through the series (issue 36, second half of Mother's Milk's origin story), but no real spoilers. Garth loves his exposition.