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I have a 4.10 rear and when I replaced my rear tires from 30.5" to 31.5" I gained about 1-1.5 mpg on the highway and about a .5mpg gain in the city. With your truck "underloaded" you will probably pick up 2-4 mpg on the highway with no ill effects if you drop a size on your differential.
I do not believe the shift parameters are based off of what the abs reads either, so your shifting should ok, but you might need to have your speedometer adjusted.
If it were me, I would only do it if the amount I would pay to have the rear changed pay me back in 3 years or less. If you know how to change it yourself, even better.
2001 Ford E350 7.3 Extended Cargo Van
BTS Transmission, PHP Minotaur package, 4" exhaust/downpipe, Honey Badger jr., FRX, HPX, AIH delete, Fuel bowl mod, Hypermax Boost/Pyro gauge, 4.10 rear.