Xanthorrhizol is a sesquiterpenoid isolated from Curcuma xanthorrhiza that has been known to possess anti-inflammatory and anti-carcinogenic effects. In this work, we have found that xanthorrhizol reduced superoxide anion generation by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated HL-60 cells and exerted a dose-related inhibition of His reversion in Salmonella typhimurium TA102 induced by tert-butylhydroperoxide (t-BOOH) and hydrogen peroxide. Pretreatment of xanthorrhizol significantly decreased the incidence and the multiplicity of mouse skin tumors stimulated by TPA for 19 weeks after a single application of dimethylbenz[a]anthracene (DMBA), and mitigated the expression of epidermal ornithine decarboxylase in the skins. These results demonstrate that xanthorrhizol may be a potent cancer chemopreventive agent.