I have spent several hours searching truck forums and researching the Mythbusters findings as well as other more scientific ones. The amazing thing is all have different views, even Mythbusters did their test twice with different results each time.
However, no one I have found has done any PU bed testing while towing an aerodynamic trailer.
I just installed a Tonneau cover on my new PU. The PU only has 1k miles on it, and I haven't even checked MPG yet, but I just (today) returned from a 150 Mile drive with the cover on. I did the same drive 2 weeks ago, and on the same flat, long smooth road I traveled previously, I did notice a different tachometer reading between the two trips at 60 MPH.
I have been using the tach to watch shift points with my 5sp manual transmission as well as watching rpm's at different speeds so this slight difference (less than 100 rpm's) between with and without the tonneau, caught my eye.
I know there are so many variables, and my observation was not very scientific, but I am leaning toward the tonneau offering at least some help (lower RPM should equal lower MPG) for the PU only, but that may prove the opposite while towing a tear.
The tonneau is a roll-up type, and I can try the rpm thing over a given stretch of road on the same day with it on or off.
This could prove to be even more scientific than trying to accurately check MPG with or without the tonneau, and i'll try again when I actually finish my tear
Larry C