The beneficial health effects of red wine have been attributed to the antioxidant activity of its polyphenols. The present study investigated the effects of a standardized freeze-dried powder made from fresh grapes, rich in grape-specific polyphenols and free of alcohol, on oxidative stress, atherogenicity of macrophages, and the development of atherosclerotic lesions in apolipoprotein E deficient (E(0)) mice. Thirty E(0) mice were assigned to 3 groups. Mice consumed water alone (control), 150 mug total polyphenols/d in the form of grape powder (grape powder), or the equivalent amount of glucose and fructose (placebo) in drinking water for 10 wk. Consumption of grape powder reduced the atherosclerotic lesion area by 41% (P < 0.0002) compared to the control or placebo mice. The antiatherosclerotic effect was at least partly due to a significant 8% reduction in serum oxidative stress, an up to 22% increase in serum antioxidant capacity, a significant 33% reduction in macrophage uptake of oxidized LDL, and a 25% decrease in macrophage-mediated oxidation of LDL relative to controls. Grape powder directly protected both plasma LDL and macrophages from oxidative stress in vitro. We conclude that polyphenols from fresh grape powder directly affect macrophage atherogenicity by reducing macrophage-mediated oxidation of LDL and cellular uptake of oxidized LDL. Both of these processes can eventually reduce macrophage cholesterol accumulation and foam cell formation and hence attenuate atherosclerosis development.