Regular and moderate wine consumption is one of the explanations suggested for the lower incidence of cardiovascular events in France compared with other industrialized countries. We evaluated whether alcohol alone or combined with red wine polyphenols reduced plaque size and/or attenuated thrombotic reactivity at the site of advanced atherosclerotic lesions. Red wine extract, or purified (+)-catechin with alcohol, or alcohol alone, was added for 12 weeks to the drinking water of apoE-deficient (apoE(-/-)) C57BL/6 mice and wild-type counterparts. In the apoE(-/-) mice, all alcohol-containing mixtures were associated with a larger size of aortic atherosclerotic lesions. On the other hand, red wine extract and (+)-catechin significantly inhibited blood thrombotic reactivity (P<0.05) as assessed in a cylindrical perfusion chamber model of experimental thrombosis: area reductions in cross-sectional surface of the ex vivo thrombus were 64% and 63%, respectively. In the wild-type mice, red wine extract and (+)-catechin tended to reduce thrombogenicity, which was on the whole less marked than in the apoE(-/-) mice. These findings suggest that a moderate and regular consumption of red wine may protect against clinical cardiovascular events, mainly by attenuating the thrombogenic response rather than by reducing the development of atherosclerotic lesions. This antithrombogenic effect may include normalization of the abnormally high thrombogenic responsiveness in apoE(-/-) mice as well as a direct antithrombotic effect.