For cruising down the highway, I believe Atikovi's take is the simplest and best answer. If the cost saving offsets the loss in fuel economy it's fine. As a very frequent road-tripper, I've seen E85 up to 30% cheaper, which makes it a no-brainer in most cases. On the other hand, one of my local stations sells E85 for 10 cents less than regular unleaded per gallon. No thanks.
These discusssions often presuppose every E85 outlet is actually serving up E85. When I still had my 2014 T&C, most (not all) pumps I used had a disclaimer label stating something to the effect of the fuel consists of ethanol content between 51% and 85%. As someone who tracks every tankful, it seems the alcohol content indeed varies.
For instance, I'm pretty much a speed limit/cruise control/right lane kind of guy. With a tankful of regular unleaded and a standard load (me, wife, and some luggage) I'll typically cover 430-440 miles before having to refill with 17-18 gallons, which puts me in that 24-25 mpg range. This is my rough benchmark.
There's a Meijer station I frequent in Milwaukee for its cheap E85 before heading back south. On this fuel we pretty consistently eke out 380-390 miles, good for 21-22 mpg...up to a 16% loss. I've used this station dozens of times over the past 6-7 years, and the results are pretty much the same, so it's kind of my E85 benchmark.
Another station I hit rather frequently is a Casey's in rural Arkansas, whose E85 is often 25% less than their unleaded. Surprisingly, every time I used their E85 the van exceeded 400 miles of range, once hitting 425 headed south. I'm pretty sure their ethanol content is less than 85%.
What does this all mean? I don't know...just rambling on my E85 experiences. In my case, as a careful, economy-minded driver, E85 has been a satisfactory fuel choice if 1) you're highway cruising, and 2) the cost is at least 20% lower than regular unleaded.
