Saudi and Egyptian pomegranate juice (APJ and EPJ) contains potent polyphenols, antioxidants that were found to reduce serum and macrophage oxidative stress. The protective effects of APJ and EPJ against atherogenicity were evaluated by feeding mice a hypercholesterolemic diet that was supplemented with PJ.PJ consumption reduced mice serum triglycerides (TG), total cholesterol (TC) and (low density lipoprotein (LDL-c) and increased the high-density lipoprotein (HDL-c) when compared to mice with a control or atherogenic diet. The risk ratio and atherogenic index were significantly lower in both APJ or EPJ supplemented groups. Paraoxonase 1 (PON1), which remains associated with HDL, had a significant increase in activity in mice supplemented with PJ, compared to mice with aatherogenic diet (AD). PJ consumption significantly reduced lipid peroxidation and increased glutathione levels. The reduction in lipid peroxidation varied from 57 to 76%. PJ supplementation reduced peritoneal macrophage (MPM)-mediated oxidation of LDL by 68 to 82% and decreased mouse MPM Ox-LDL uptake by 31 to 48%. A significant up-regulation of macrophage PON2 activity was induced by PJ reducing the macrophage oxidative stress. In conclusion, PJ consumption resulted in anti-oxidative and anti-atherogenic effect on serum and macrophages, which could prevent atherosclerosis and coronary heart diseases.