Resveratrol (3,4',5-trihydroxystilbene) is a phytoalexin present in some red wines. Like other phenolic substances, this compound is assumed to protect against atherosclerosis by reducing the peroxidative degradation of low-density lipoproteins (LDL). The in vitro efficiency of resveratrol was found to be mainly due to its capacity to chelate copper, although it also scavenges free radicals. In this study, we examined the ability of the compound to associate with lipoproteins in vitro. Trans-resveratrol added to plasma was distributed between subsequently isolated lipoproteins with a linear dose-response curve. The concentrations as expressed on a protein basis increased with the order of their lipid content: high-density lipoproteins (HDL) < LDL < very low-density lipoproteins (VLDL). This finding reveals the lipophilic character of resveratrol. Other assays showed that resveratrol added to plasma prior to fractionation was, as expressed on a protein basis, more associated with lipoproteins (d < 1.21 g/mL) than with lipoprotein-free proteins (5.5 +/- 0.7 vs 2.2 +/- 0.4 nmol/mg protein). On the other hand, resveratrol inhibited the formation of thiobarbituric acid reactive substances (TBARS) in preparations containing phospholipid unilamellar liposomes oxidized by the water-soluble radical generator 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH). A linear dose-response curve was obtained up to 30 microM when the antioxidant was added in the final preparation and up to 200 microM when added before preparing liposomes in order to facilitate its incorporation. This suggests that the soluble fraction of resveratrol scavenged free radicals in the aqueous phase before attacking PUFA and within membranes. Taken together, the present data support the hypothesis that resveratrol may be efficient at different sites: in the protein and lipid moieties of LDL and in their aqueous environment.