Postprandial hyperlipemia is a well-defined risk factor for atherosclerosis. A reasonable contributing mechanism could involve the postprandial increase of plasma lipid hydroperoxides (LPO) affecting the oxidant/antioxidant balance and increasing the susceptibility of LDL to oxidation. Wine has been shown to prevent both these events. The present study was designed to investigate the effect of supplementing a meal with grape seed proanthocyanidins (the main phenolic antioxidant of red wine) on plasma postprandial oxidative stress. In two different sessions, 8 healthy volunteers consumed the same test meal rich in oxidized and oxidizable lipids without (control) or with 300 mg of a proanthocyanidin-rich grape seeds extract (GSE). Lipid hydroperoxide concentration, antioxidant status, and LDL resistance to oxidative modification were measured in postprandial plasma. The content of LPO in chylomicrons was 1.5-fold higher after the control meal than after the GSE-supplemented meal. Plasma LPO increased only after consumption of the control meal. The plasma antioxidant capacity increased in the postprandial phase only following the GSE supplemented meal. LDL isolated 3 h after the control meal tended to be more susceptible to oxidative modification (but the difference did not reach statistical significance). An opposite trend was observed following the GSE supplemented meal. In conclusion, the supplementation of a meal with GSE minimizes the postprandial oxidative stress by decreasing the oxidants and increasing the antioxidant levels in plasma, and, as a consequence, enhancing the resistance to oxidative modification of LDL.