For older cars and cars with smaller engines, the drag of the AC compressor is greater... leading to higher fuel consumption with the AC on (heck, with Nissan Sentras with the Calsonic compressor, it could rob a ton of horsepower). For bigger-engined vehicles, it seems like less of a problem... but setting the AC to the lowest comfortable setting (highest temperature at lowest fan speed that still feels cool from all seats) is always a good idea...