Opuntia humifusa, member of the Cactaceae family, was previously demonstrated to have radicalscavenging, anti-inflammatory and anti-proliferative effects in in vitro models. It was suggested that O.humifusa could function in the prevention of carcinogenesis. To investigate the in vivo chemopreventiveeffect of O. humifusa, mice were fed a diet containing either 1% or 3% following 7, 12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) induction of skin carcinogenesis.Significant decrease in the numbers of papilloma and epidermal hyperplasia were observed in mice fed withO. humifusa, compared to the control group. O. humifusa also upregulated high total antioxidant capacityand level of phase II detoxifying enzyme such as superoxide dismutase and glutathione S-transferase activityin the skin. Lipid peroxidation activity level was measured in skin cytosol and significantly inhibited in 3%OH fed group compared to the control group. These results suggest that O. humifusa exerts chemopreventiveeffects on chemical carcinogenesis in mouse skin and that prevention effects are associated with reduction ofoxidative stress via the modulation of cutaneous lipid peroxidation, enhancing of total antioxidant capacityespecially in phase II detoxifying enzyme system and partial apoptotic influence.