Resveratrol is believed to be partially responsible for the French paradox--the low risk of cardiovascular disease despite a high-fat diet in the French population. Recently, resveratrol has also been discussed as a life-span booster in several organisms. Age-related diseases are associated on the cellular level with senescence. We, therefore, hypothesized that resveratrol is vasoprotective by counteracting endothelial cell senescence. Surprisingly, we observed that chronic treatment with resveratrol (10 microM) was prosenescent in primary human endothelial cells. Resveratrol induced elevated reactive oxygen species (ROS) levels that were associated with and causally linked to an accumulation of cells in the S phase of the cell cycle, as measured by flow cytometry. We further show that cell accumulation in S phase leads to increased ROS and finally senescence. Using an siRNA approach, we clearly identified two NADPH oxidases, Nox1 and Nox4, as major targets of resveratrol and primary sources of ROS that act upstream of the observed S-phase accumulation.