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OK, I'm a newbie here, BUT: got a 2000 f250 6 speed & 3.73 rear end that I claim @ 20+ mpg city for 135000 miles. Back before fuel reformulation i got 25 mpg stock summer. Not a lot of differences between the 250 and 350. In this case, axle spacers and door stickers. Yes I have the turbo and intercooler, but don't run a lot of boost.
stuff I did: cab top campershell with BOOT not windows. played with raising and lowering. raising it cost me 5% for every inch up, lowering it did approx the same for increases. I suggest using the 250 rear axle spacers which lowers the rear about 2" at a mild load capacity loss which can be avoided with helper springs\airbags. NEVER go above 2000 rpm, try to stay at 1750 which is theoretical best efficiency if you can trust Ford owner's documents. I run really lean because of a fuel pump issue (about -28 on LTFT)
Heavy it responds best with hypermile techniques because all that mass doesn't want to stop. I just whine a lot starting off and while going up hills.
YMWV
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