Best is, AC off windows up.
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I believe the "windows up, AC on is more efficient" statement that is often heard applies to smaller cars that are typically more aerodynamic than our trucks. I seriously doubt it would be true for us. I've watched the trip computer pretty closely, and rarely can I make it change the instantaneous MPG by turning AC on or off. Based on that alone, the impact of using AC must be something less than 1 mpg. If my potential savings (windows up) is less than 1 mpg, and I'm losing some of that by rolling down the windows, then any net savings must be very small (<0. 5 mpg).
I run without AC early in the morning, or at other times when I can with reasonable comfort, but if it gets hot enough that I need the window full open, the AC is coming on.