Multiple lines of evidence from laboratory studies suggest that resveratrol, a polyphenolic antioxidant present in grapes, has potent chemopreventive activity. Resveratrol has been reported to inhibit chemically-induced carcinogenesis in mouse skin, but the underlying mechanisms remain unclarified. Since an abnormally elevated level of cyclooxygenase-2 (COX-2) has been implicated in carcinogenesis, we investigated the effect of resveratrol on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 expression in mouse skin. Pretreatment of dorsal skin of female ICR mice with resveratrol inhibited TPA-induced COX-2 expression in a dose dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by resveratrol, we examined its effect on TPA-induced activation of mitogen-activated protein kinases (MAPK) and transcription factors which regulate COX-2 expression. Resveratrol pretreatment resulted in a decrease in the phosphorylation of extracellular signal-regulated protein kinase (ERK) as well as the catalytic activity of ERK and p38 MAPK. In addition, resveratrol prevented TPA-induced DNA binding of activator protein-1 (AP-1). Taken together, suppression of COX-2 expression by blocking the activation of MAPKs and AP-1 may represent possible molecular mechanisms responsible for previously reported anti-tumor promoting effects of resveratrol on mouse skin carcinogenesis.