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Reliability and efficiency?.. Your best bet is a 300 inline six with a manual trans. Decent MPG and torque to get the rig moving.
Swap in the late-model EFI system or go aftermarket with the likes of MSD Atomic, Edlebrock E-street, FAST EZ-EFI, or Powerjection III from Professional Products. Others include Howell EFI or Megasquirt.
Of course do the typical exhaust, intake, and ignition mods.
If you are looking for a (relatively) fuel efficient injected setup, I would be looking at the late 80's to early 90's 302's or the 4.6. These two options are really easy to physically bolt in and there is really good aftermarket support for swap wiring harnesses. Or you could look into the injected 300 I6. I don't know much about swapping in the injected version, but that is as close to a bulletproof engine as you will ever find. Some of these trucks came with a I6 or a 302, so the parts are out there to simply bolt those in. Or if you are looking into doing the crown vic front end, the 4.6 bolts right into that. The later model crown vics are getting 27 or so mpg's out of the 4.6. If you swap out the whole drivetrain, then the big obstacle you are going to have to getting fuel mileage is the aerodynamics of the truck. A 2wd F100 is really not as heavy as you would think, but has the aerodynamic profile of a brick. I don't know what kind of timeline you are working with, but if you need them, I will eventually have a set of 302 perches up for grabs as i am going to be swapping the 4.6 DOHC Mark VIII motor into mine, its just a really slow moving project right now.
Since aero was bought up by mkoch96, I thought I'd share some potential mods to increase aero efficiency on a 2WD...
Modify the grill and front end to reduce the unnecessary openings - close off all the grill except for what is needed for the radiator.
Lower the truck to reduce frontal area and exposing the aero-dirty undercarriage.
Add an air dam.. yes it increases frontal area but smooths air flow. There is a point of diminishing returns however.
Add an underbelly tray/belly pan to at least the radius arm crossmember to smooth the underside and reduce turbulence.
Add a reverse cowl hood to bleed off air in the engine compartment.
Delete the roof rails
Slick up the body - flush-mount door handles, emblem deletes,small or aerodynamic mirrors, antenna, gas cap etc.
Weight in terms of MPG is also an issue:
... a dock bumper weighs upwards of 80 lbs
... an FE intake weighs 82 lbs
... big tires have lots of rolling resistance and unsprung weight
... steel vs aluminum wheels
... extra fuel tanks
OK - Great advice - I have a 91 bronco with a blown engine (rod knocking). I'm doing a junkyard swap on that right now - so I have a core 5.0 efi engine just laying there in a puddle of oil begging to be rebuilt.
You can modify a stock EFI harness, there are about 15 wires that need to be connected to make it all work. But there are engine swap harnesses available for this as well which make it easier. Here's a little info:
The link on that page to their product page to buy a harness seems to be unavailable. I think Painless makes a swap harness as well.
A few years back I swapped a 5.0 into an '89 Ranger using a stock '89 Mustang harness. If I had it to do again I'd fork over the bucks for a swap harness as I ran into a number of difficulties in trying to integrate the stock Mustang engine harness with the stock '89 truck harness. I never did get all the bugs worked out of my swap and lost interest, and it sits in the carport, unfinished and untouched for at least the last 5 years or so.
I had a 94 f150 with the 300 I6 fuel injected , wouldn't win a race against a Prius but had tons of TQ , use to load it up with two harleys and couldn't tell they were in the back .