The ability of the potent antioxidant, 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII), to inhibit tumor formation by topically-applied benzo[a]pyrene was evaluated using a complete carcinogenicity mouse skin bioassay. THII was administered by direct application to the skin, in the food or through the drinking water. In each case, THII increased the average time until the appearance of tumors by 4 weeks, and also decreased the total number of tumors compared with benzo[a]pyrene alone. These protective effects corresponded with the ability of THII to inhibit benzo[a]pyrene- or 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity, a biomarker of tissue proliferation in skin of the treated animals. This is the first report of an antioxidant administered in food or water inhibiting chemically induced skin carcinogenesis.