One of the strongest arguments for the 300 is that it can do a V8's job while getting better gas mileage overall. I've noticed that with most engines there comes a point where you are loading it up enough that the fuel economy falls off badly, possibly also due to the gearing required to make it work right. Usually I would consider anything above that weight point diesel territory.

I was rather entertained by the fact that my neighbors 20,000lb gvw 1966 F600 came with the 300 I-6 though it may have had something do to with the gearing of the Clark 5spd overdrive transmission and 6.8 rear end gears, (though it also has massive tires which offset that). I have no idea what kind of mileage it would get and he didn't know.