My opinion--yours may differ--
Shocked that no has said if the OP is remotely considering a fifth wheel bigger than the very smallest ones, he should get a 350/3500 because bed weight capacity will be a limiting factor with 250/2500s. Our 2012 F-350 SRW CCSB 6.7 diesel consistently gets 11 towing, 15 around town, and 20 at interstate speed limits empty. It drops to 19 when I speed on the interstate and I've gotten as low as 10 on the highway simply pushing a head wind empty. The early days of emission controls (2006 - 2010 with Ford and through 2012 with RAM pre-DEF) got poor mileage. All three eventually got that under control and get amazing mileage considering the huge HP numbers they put out. Mileage is going to be a factor of how much you put your foot into it and how much load you're moving, especially after the trailer load starts exceeding the weight of the truck.