The objective of this study was to determine the chemopreventive effects of sarcophine-diol (SD) on 7,12-dimethylbenz(a)anthracene initiated and 12-O-tetradecanoylphorbol-13-acetate promoted skin tumor development in mice and its possible mechanisms of action. SD pretreatment significantly (P<0.05) decreased skin papilloma development during promotion phase. SD significantly (P<0.05) increased caspase-3 and decreased cyclooxygenase-2 during initiation phase or promotion phase. SD significantly (P<0.05) increased caspase-8 during promotion phase. SD resulted in a 95% reduction in 12-O-tetradecanoylphorbol-13-acetate-induced DNA synthesis. SD could be an effective chemopreventive agent for skin cancer by enhancing apoptosis and decreasing cell proliferation.