Here's my experience with tall geared (don't start Doc) heavy vehicles.

I had a 79 F100 with a 300 inline 6, 3 on the tree with 2.75 gear and a 28" tire. Had a Clifford intake with a 600 4150 Holley with headers and 2.5" exhaust. 10 MPG hi-way that's it that's all. Vacuum gauge read 10" at speed. Changed the rear to 3.50's and it got 16+. Vacuum gauge now reads 16-18" at speed.

My take on it is this: A 300 makes lots of torque BUT is a bit shy in the HP dept. It takes HP to go fast and in order to make the HP number required to run 65 at 2150 RPM required a larger throttle opening than it did with 3.50's even tho it now ran 2750 to do the same speed. the vacuum gauge tells the tale. 10" vs 16+". 1" of vacuum is 1 MPG give or take so try it with a few different ratios if you have them to try. You might be surprised at what you find, I know I was.

Kevin