I can relate, I own two Harley's (Sportster, Fatboy Lo) and love them both. I also have an F6B and love that too for different reasons. I really appreciate the personality the big twins offer, say what you will about the MoCo but they build bikes that look good and offer a distinctive ride (e.g. "personality").

The Honda is definitely the long haul bike in my stable, although many on the forum will attest to its relative nimbleness for an enormous bike. I won't argue, it does handle well for its size. But its my bike of choice if I'm racking up the miles or just intend to be out all day.

Fatigue will be minimal because vibration is non-existent. Gas mileage is so-so, but the tank is around 6 gallons so not a big deal. Ergonomics work for me, and I'm used to big bikes so size is not a concern. Its typical Honda: as close as it gets to mechanical perfection, so peace of mind is always there.

In my opinion you can't go wrong with the F6B if you are looking for a large cruiser/touring bike. Good luck with your decision.