Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL (ox-LDL) and TNF elicited significant increases in caspase 3/7 activity in cultured endothelial cells, which were prevented by resveratrol pre-treatment (10^-6 to 10^-4 mol/). The protective effect of resveratrol was partially reversed by glutathione peroxidase inhibitor mercaptosuccinate suggesting a role for antioxidant systems in the anti-apoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H₂O₂ levels and H₂O₂-mediated apoptotic cell death induced by oxidative stressors (exogenous H₂O₂, paraquat, ultraviolet light). Resveratrol treatment up-regulated the expression of glutathione peroxidase and catalase in cultured arteries, whereas it had no significant effect on expression of SOD isoforms. Resveratrol also effectively scavenged H₂O₂ in vitro. Thus, resveratrol seems to increase vascular oxidative stress resistance by scavenging H₂O₂ and preventing oxidative stress-induced endothelial cell death. We propose that the anti-oxidant and anti-apoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects.