I had a couple E250 vans, one with the 4.6 and the other with the 5.4.
Only issue I had was at 57,000kms (just within warranty!) the pinion in the rear diff decided to tear itself up in the 4.6L van. Dealer redid the whole rear end, only to have the ring gear fail on account that the tech who did the install didn't set the pre-load properly and the dealer covered the cost of that ($880 for full rebuild) at 82,000kms. It was a 2006 and I sold it two years back with just over 200,000kms and no other issues. The 2007 5.4L E250 had no problems with similar mileage.
It's a bit funny as I looked at a 12 pass E350 (2010) with fairly low miles last week to replace my Durango as a tow machine. It needed a few small fixes (a few seat tears, tires were nearly bald) and the seller wouldn't budge on the price to factor in the problems so I walked away.
'11 Ram Quad Cab 4x4 SXT 5.7L HEMI (stock); 48,500m
'06 Pontiac G6 GT 3.5L 220hp; 64,000m
'12 Chrysler 200 Limited 3.6L 283hp; 28,000m
'99 Taurus 3.0L 2V Vulcan 145hp; 154,300m - Traded
Amsoil in all vehicles!