Heme-mediated oxidative modification of low-density lipoprotein (LDL) plays a crucial role in early atherogenesis. It has been shown that hydrogen sulfide (H(2)S) produced by vascular smooth muscle cells is present in plasma at a concentration of about 50 micromol/L. H(2)S is a strong reductant which can react with reactive oxygen species like superoxide anion and hydrogen peroxide. The current study investigated the effect of H(2)S on hemin-mediated oxidation of LDL and oxidized LDL (oxLDL)-induced endothelial reactions. H(2)S dose dependently delayed the accumulation of lipid peroxidation products-conjugated dienes, lipid hydroperoxides (LOOH), and thiobarbituric acid reactive substances-during hemin-mediated oxidation. Moreover, H(2)S decreased the LOOH content of both oxidized LDL and lipid extracts derived from soft atherosclerotic plaque, which was accompanied by reduced cytotoxicity. OxLDL-mediated induction of the oxidative stress responsive gene, heme oxygenase-1, was also abolished by H(2)S. Finally we have shown that H(2)S can directly protect endothelium against hydrogen peroxide and oxLDL-mediated endothelial cytotoxicity. These results demonstrate novel functions of H(2)S in preventing hemin-mediated oxidative modification of LDL, and consequent deleterious effects, suggesting a possible antiatherogenic action of H(2)S.