It has been suggested that a high-fat meal may acutely impair endothelium-dependent vasodilation and that this impairment may be prevented by concomitant intake of antioxidants. Because red wine contains antioxidant polyphenols and may reduce cardiovascular disease, we examined the effect of red wine on postprandial endothelial function. Using a crossover design, 13 healthy volunteers consumed a high-fat meal (0.8 g fat/kg body weight) with red wine (3 ml/kg) or an isocaloric control beverage on 2 separate days, 1 week apart. Flow-mediated dilation of the brachial artery was examined by vascular ultrasound at baseline and at 2, 4, and 6 hours after the meal. At these times, flow-mediated dilation with the high-fat meal and control beverage was 9.5 ± 5.0%, 7.9 ± 5.1%, 6.8 ± 3.6%, and 7.3 ± 4.6%, respectively (nonsignificant trend). There was also a nonsignificant trend for flow-mediated dilation after the high-fat meal with wine: 8.0 ± 4.1%, 5.7 ± 4.7%, 6.4 ± 3.1%, and 6.9 ± 3.8%, respectively. There was no difference in the effects between wine and the control beverage (p = 0.77). Triglycerides increased 2- to 2.7-fold over baseline (p = 0.0001) with a peak occurring 5 hours after the high-fat meals. In contrast to previous studies, the present study did not demonstrate a significant effect of a high-fat meal on endothelial vasomotor function in healthy subjects. Under these conditions, we did not demonstrate a beneficial acute effect of red wine on endothelial function.