Background—A growing body of evidence from animal studies supports the hypothesis that oxidative stress-mediated mechanisms play a central role in early atherogenesis. In contrast, clinical trials with antioxidant vitamins have not produced consistent results in humans with established atherosclerosis.Methods and Results—Low-density lipoprotein receptor-deficient mice (LDLR KO) were fed a high-fat diet for 3 months to induce atheroma. At this time, 1 group of mice was euthanized for examination of atherosclerosis, and 2 other groups were randomized to receive high-fat diet either alone or supplemented with vitamin E for 3 additional months. At the end of the study, LDLR KO on a vitamin E-supplemented fat diet had decreased 8,12-iso-isoprostane (iP)F2&agr;-VI and monocyte chemoattractant protein-1 levels, but increased nitric oxide levels compared with mice on placebo. No difference in lipid levels was observed between the 2 groups. Compared with baseline, placebo group had progression of atherosclerosis. In contrast, vitamin E-treated animals showed a significant reduction in progression of atherosclerosis.Conclusions—These results demonstrate that in LDLR KO, vitamin E supplementation reduces progression of established atherosclerosis by suppressing oxidative and inflammatory reactions and increasing nitric oxide levels.