I have to say, I love my E450 Super Duty. The tires are normal sized (although there are 6 of 'em); the Ford Powerstroke is killer; with a backup camera I'm sure I'll be able to park in reasonable spaces (although I haven't tried that yet); and now that I've gotten rid of the bi-fold doors, I really love the interior space.
If I were to do it all over again: I'd pay more attention to rust; I'd go with a Duramax (I'd love the 6.6L and Allison tranny!); and I'd try to find one with a stock passenger seat/door, like this:
I do worry about major engine work. The drivetrain is really shoehorned in there, so I'll probably have to drop the engine to do anything significant. That's pretty much the only drawback I've come across though.