It depends.
I have 3 choices of commuting routes. The longest route to work (20.1miles), which has 15 miles of freeway driving (6 miles @ 75 MPH
up hill and generally into the wind and 9 miles @ 65 ) nets the worst MPG and (duh) consumes the most fuel. The two shorter routes - one with 9 freeway miles @ 65 MPH (18.5 miles), and one with NO freeway miles (16.5 miles - driving through town) net about the same MPG. I take the shorter route to save fuel.
Driving home from work, I generally take the 18.5 mile (9 miles @ 65 MPH) route to avoid in-town traffic at 4:00 PM. If I "take the long way home", I keep my speed @ 65 MPH in the 75 MPH zone. It nets about the same MPG as the medium commute, burning about 4.6 more ounces of fuel. That's a small price to pay for not having to deal with 200 aggressive @$$holes on the shorter routes.
And when I quit taking the long (and fast) route, I began to regularly exceed 30 MPG with my 4.0 liter Ford Mustang commuting to work.