Tip-up all the way for me. Since I carry right front pocket all of the time. Having the blade up against the rear pocket seam is a secondary safety.
If a knife was offered with switchable right-side tip carry, I move it to tip-up. I haven't had too many problems with this, mainly on cheaper knives one runs the risk of stripped screws though.
Most of the knives I carry are on the larger side, 3.5-inch or more. Tip-up has always worked for me. I even like it on the massive 5.5- and 6-inch Cold Steel's too.
I generally won't buy a knife with tip-down-only, with very rare exceptions. I bought a Kershaw Junkyard Dog a while ago and was pleasantly surprised at how comfortable the handle was. The pocket clip didn't get in the way at all.
Usually tip-down only "pokes" my hand on larger knives. It does work well on smaller knives like the (long-discontinued) Spyderco Caly Jr.
As much as it would be nice for every folder out there to have 4-way pocket clip mounting. It isn't practical for various reasons:
Sometimes the handles are too narrow.
Sometimes the locking system doesn't allow easy lock button access for tip-down, such as Axis-Locks and the ball-bearing Lock.
Back to the locking systems: Some locking systems hold the blade shut in the closed position, such as lockbacks, Axis-Lock, Arc-Lock and ball-bearing.
However, linerlocks usually need a ball-bearing detent to hold the blade shut. In tip-down, this can be a safety hazard if the pivot loosens up over time.
I have a coworker that was carrying a Spyderco Military that opened up in his pocket. He wasn't pleased about that at all!
Tip-up has a definite advantage: It allows for the middle, ring and pinky fingers something to "anchor" onto for opening.
The main disadvantage to tip-up is that it can leave a larger amount of the handle sticking up out of the pocket.
I would like say that I am pleased to see companies offering tip-up that used to be tip-down-only: CRKT and Benchmade on their linerlocks.