One of the key elements of Mediterranean diet is the use of wine, usually taken with foods. Besides the evidence from human experience and ancient medicine, modern experimental data support the notion that the most striking effect of wine in protecting against cardiovascular disease involves the reduction of oxidative damage to plasma lipoproteins. This oxidative damage is thought to be mediated by eating foods containing oxidized lipids. In fact, eating a meal containing oxidized lipids increases the plasma level of lipid hydroperoxides and increases the susceptibility to oxidation of LDL. The postprandial increase of LDL-, an oxidatively modified form of LDL, where apoB is unfolded and sinking in the core of the particle, is a valuable biomarker for this food-derived oxidative stress in plasma. Wine, taken with foods minimizes the postprandial rise of lipid hydroperoxides and LDL- and abolishes the increase of LDL oxidability. Among wine antioxidants, the best candidates for providing an antioxidant effect are procyanidins. These compounds are considered better antioxidants than the corresponding monomers containing catechol groups. This is due to the hydrogen transfer mechanism for the radical-scavenging reaction, which renders the reaction more specific for peroxyl radicals and pH independent. Moreover, the fast intramolecular disproportion among aroxyl radicals pulls the antioxidant reaction by both decreasing the oxidation potential and increasing the rate of the reaction. Apparently, wine procyanidins are active in preventing lipid oxidation of foods while in the digestive tract, thus preventing the postprandial plasma rise in oxidants. The likely limited bioavailability of these compounds, therefore, does not affect their relevance as key elements for optimizing nutrition and reducing risk of atherogenesis. Accordingly, studies with rabbits fed a high cholesterol diet show that grapeseed procyanidins are strongly protective not only in terms of reducing plasma lipid peroxides, but they also markedly inhibit lipid-laden foam-cell deposition. Drinking wine at meals provides this kind of protection, and the final benefits are realized by the prevention of the development of atheromatous lesions even under conditions of hypercholesterolemia.