The free radical scavengers N-acyl dehydroalanines (AD compounds) were examined for their effect on several 12-O-tetradecanoylphorbol-13-acetate (TPA) elicited events in mouse skin. The induction of oxidant production by TPA in isolated mouse epidermal cells was reduced by approximately 70% by 1 mM paramethoxyphenyl-acetyl dehydroalanine (AD5) and 80% by 1 mM parasulfoxyphenyl-acetyl dehydroalanine (AD19). These AD compounds also completely suppressed the TPA-dependent stimulation of prostaglandin E2 synthesis in primary cultures of epidermal cells. Single and multiple topical applications on the dorsal skin of SENCAR mice of either AD5 or AD 19 inhibited TPA-induced epidermal hyperplasia but failed to inhibit epidermal ornithine decarboxylase induction. When used with TPA on initiated mice, AD19 did not inhibit papilloma formation; however, after 40 weeks of promotion, the carcinoma incidence was reduced by 50% in the AD19 group. These results suggest that reactive oxygens may be more important to the conversion of benign to malignant tumors than in the initial development of the benign tumors.