Various phenols, notably p-cresol, and two non-phenolic compounds have been found to stimulate the aerobic reoxidation of cytochrome b5, reduced by NADH, in rat liver microsomes having a high activity of stearyl CoA desaturation. This stimulation is accompanied by simultaneous increases in the oxidation of NADH and consumption of molecular oxygen. The phenols added also seem to be oxidized. Evidence has been obtained that cytochrome b5 located in a microsomal vesicle undergoes oxidation independently of that present in the other vesicles during the phenol-stimulated process. As in the similar stimulation of cytochrome b5 reoxidation by stearyl CoA, the phenol effect is inhibited by cyanide. The magnitude of phenol effect can be correlated with the stearyl CoA desaturation activity of the microsomes; it is negligible in liver microsomes from fasted rats, but can be induced profoundly by refeeding the animals on a high-carbohydrate diet. The phenol effect is also detectable in adipose tissue microsomes, which show a high desaturation activity. It is concluded that the phenols interact with the cyanide-sensitive factor, the terminal enzyme of the microsomal desaturation system, resulting in an increased utilization by oxygen of electrons of reduced cytochrome b5. Since the phenol effect is depressed by low concentrations of stearyl CoA, the cyanide-sensitive factor seems to react with stearyl CoA in preference to the phenols.