Liposomal glutathione, but not the control liposomes (with no glutathione), dose-dependently inhibited copper ion-induced low density lipoprotein (LDL) and HDL oxidation. As peroxidase activity was found to be present in both LDL and HDL, it has contributed to the anti-oxidative effects of liposomal glutathione. In-vitro, no significant effect of liposomal glutathione on J774 A.1 macrophage cell-line oxidative stress and on cellular cholesterol metabolism was observed. In contrast, in the atherosclerotic apolipoprotein E-deficient (E(0)) mice, consumption of liposomal glutathione (12.5 or 50mg/kg/day, for 2 months), but not control liposomes, resulted in a significant reduction in the serum susceptibility to AAPH-induced oxidation by 33%. Liposomal glutathione (50mg/kg/day) consumption also resulted in an increment (by 12%) in the mice peritoneal macrophages (MPM) glutathione content, paralleled by a significant reduction in total cellular lipid peroxides content (by 40%), compared to placebo-treated mice MPM. MPM paraoxonase 2 activity was significantly increased by 27% and by 121%, after liposomal glutathione consumption (12.5 or 50mg/kg/day, respectively). Analyses of cellular cholesterol fluxes revealed that, liposomal glutathione (12.5mg/kg/day) consumption, decreased the extent of oxidized-LDL (Ox-LDL) uptake by 17% and the cellular cholesterol biosynthesis rate, by 34%, and stimulated HDL-induced macrophage cholesterol efflux, by 19%. Most important, a significant reduction in macrophage cholesterol mass (by 24%), and in the atherosclerotic lesion area (by 30%) was noted. We thus conclude that liposomal glutathione possesses anti-oxidative and anti-atherogenic properties towards lipoproteins and macrophages, leading to attenuation of atherosclerosis development.