Pretreatment of mouse skin in vivo with indomethacin prevents the stimulation of epidermal cell proliferation caused by either removal of the horny layer or by application of phorbol ester TPA. The stimulatory effect of phorbol ester "TI8" is only partially inhibited, whereas the drug indomethacin has no effect on the proliferative response to skin massage or the hyperplasiogenic reaction induced by phorbol ester 4-0-methyl-TPA. These results show that depending on the stimulus, epidermal cell proliferation and hyperplasia can proceed either via an indomethacin sensitive or via an indomethacin insensitive pathway, and that indomethacin sensitivity is neither related to the hyperplasiogenic nor the tumor-promoting efficiency of the stimulus. Although TPA and 4-0-methyl-TPA are structurally closely related phorbol esters, they have different mechanisms of mitogenic action.