Chemoprevention by naturally occurring agents is a newer dimension in the management of neoplasia, including skin cancer. Solar ultraviolet (UV) radiation is the major cause of skin cancer. We recently demonstrated that resveratrol (3,5,4'-trihydroxystilbene), a polyphenolic antioxidant found in grapes and red wine, imparts protection from UVB-mediated cutaneous damages in SKH-1 hairless mice. The mechanism of action of resveratrol is not clearly understood. Here, we investigated the involvement of nuclear factor kappa B (NF-kappaB), which is known to play a critical role in skin biology and the development of skin cancer, as the mechanism of chemoprevention of UV damage by resveratrol. In the normal human epidermal keratinocytes, resveratrol blocked UVB-mediated (40 mJ/cm(2)) activation of NF-kappaB in a dose-dependent (5, 10, and 25 micro M resveratrol for 24 hours) as well as time-dependent (5 micro M resveratrol for 12, 24, and 48 hours) fashion. Resveratrol treatment of keratinocytes also inhibited UVB-mediated 1) phosphorylation and degradation of IkappaBalpha, and 2) activation of IKKalpha. We suggest that NF-kappaB pathway plays a critical role in the chemopreventive effects of resveratrol against the adverse effects of UV radiation including photocarcinogenesis.