Mythbusters has had two episodes on this,
the 1st time they did a long highway test with two identical Ford F150s running in convoy on an interstate, one with the tailgate up and one with tailgate down, until one truck ran out of gas. The tailgate up got the better MPG, but by less than 1.

The 2nd time they tested it was with a motor boat fuel flow gauge (Flowscan company) retro-fitted to a Dodge Dakota regular cab. Adam claimed he had spent considerable time 'calibrating' the Flowscan gauge.

The 2nd tests were short on a crowded California highway at 25 and 55 mph, and they tried to read the Flowscan meter by eye to find the MPG, even though the Flowscan will only read to a tenth so that the best they could do was notice differences of about 2% (0.1/5.1 gallons per hour). They did travel up and back that stretch of highway to try to cancel out head and tail winds, but could not cancel out side wind effects. These results with the Dakota & Flowscan meter by Mythbusters reported that tonneau cover and tailgate up were better than either tailgate down or tailgate off. Adam's most controversial finding with his Dakota in this 2nd set of tests was that a plastic net with about 1 inch holes in place of the tailgate seemed to be best of all....but only slightly.

After reporting these results, the Mythbusters said they were
'totally sick of doing MPG tests with pickups'
and did not want to get any more emails or letters on the subject.

You can watch any of the Mythbusters past episodes by downloading files at:

http://www2.digitaldistractions.org:8080/torrents.php?showid=mb

 

Just as an example of an 'educated guess'
about weight verus MPG
on a third Gen 5.7 Ram
weighing first 5400 lbs, then 7400 lbs
the software program 'Fuel Economy Calculator'
from Performance Trends company
predicts that at 74 mph on a level windless blacktop highway
the MPG will be about:
18.0 for 5400 lbs
17.2 for 7400 lbs

This 0.8 MPG difference due to higher weight
will be hard to detect in 'real world' driving
because
a 2.5 mph head wind,
or a 5 mph side wind
will also hurt MPG by 0.8

If you speed up slightly from 74 mph in your Ram
to about 76.4 mph
your MPG will also fall by about 0.8

In a result that many would find surprising
going from blacktop pavement to hard & stiff concrete pavement
would improve the MPG by about 1.2 at 74 mph

You can test a trial version of the Fuel Economy Calculator at:

http://performancetrends.com/

 

Thanks for tht link to all the Mythbusters episodes. There are a few that I've been wanting to revisit.