Stigmasterol (99.9% pure) was isolated from Azadirachta indica and its chemopreventive effect on 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. Skin tumors were induced by topical application of DMBA and promoted by croton oil. To assess the chemopreventive potential of stigmasterol, it was orally administered at a concentration of 200 mg/kg and 400 mg/kg three times weekly for 16 weeks. Reduction in tumor size and cumulative number of papillomas were seen as a result of treatment with stigmasterol. The average latency period was significantly increased as compared with the carcinogen-treated control. Stigmasterol induced a significant decrease in the activity of serum enzymes, such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin as compared with the control. Stigmasterol significantly increased glutathione, superoxide dismutase, and catalase as compared with the control. Elevated levels of lipid peroxide and DNA damage in the control group were significantly inhibited by administration of stigmasterol. From the present study, it can be inferred that stigmasterol has chemopreventive activity in an experimental model of cancer. This chemopreventive activity may be linked to the oxidative stress of stigmasterol. The antigenotoxic properties of stigmasterol are also likely to contribute to its chemopreventive action.