The effects of a pomegranate byproduct (PBP, which includes the whole pomegranate fruit left after juice preparation) on atherosclerosis development in apolipoprotein E-deficient (E degrees ) mice were studied. Consumption of PBP (17 or 51.5 microg of gallic acid equiv/kg/day) by the mice resulted in a significant reduction in atherosclerotic lesion size by up to 57%. PBP consumption significantly reduced oxidative stress in the mice peritoneal macrophages (MPM): Cellular lipid peroxide content decreased by up to 42%, the reduced glutathione levels increased by up to 53%, and paraoxonase 2 lactonase activity increased by up to 50%, as compared to MPM from E degrees mice that consumed only water. Furthermore, oxidized low-density lipoprotein (Ox-LDL) uptake by the MPM was reduced by up to 19%. Similar results were observed also in vitro. Treatment of J774A.1 macrophages with PBP (10 or 50 micromol/L of total polyphenols) significantly decreased both cellular total peroxide content and Ox-LDL uptake. It was thus concluded that PBP significantly attenuates atherosclerosis development by its antioxidant properties.