The aim of the current study was to investigate the biochemical changes in the plasma and retina of apolipoprotein E deficient (apoE−/−) mice supplemented with various antioxidants. Ten wild type (WT-Con, C57BL/6) and 10 apoE−/− (AE-Con) mice received drinking water. Another 40 apoE−/− animals were divided into four groups of 10 mice each and received either chromocarbe diethylamine (AE-CD, 50 mg/kg), cyaninosides chloride (AE-CC, 50 mg/kg), multivitamin complex (AE-MC, 50 mg/kg), or vitamins C and E (AE-CE, 100 mg/kg and 200 IU/kg). Cholesterol, triglycerides, and lipid peroxidation (thiobarbituric acid reactive substances [TBARS]) were measured in plasma, and TBARS and nitric oxide metabolites (NOx) concentration were determined in retinal homogenates. Transmission electron microscopy was performed to examine the retinal ultrastructure. AE-Con mice had significantly (P < 0.05) increased oxidative stress in the plasma and retina with augmented production of retinal NOx compared with WT-Con mice. Retinal TBARS decreased in the AE-MC and AE-CE animals compared with the AE-Con group (P < 0.05 and P < 0.01, respectively). Only AE-CE treatment significantly (P < 0.01) lowered retinal NOx. Morphologic retinal changes in the AE-Con group decreased in the AE-CE and AE-MC groups. There were no significant changes in the biochemical and structural parameters in the AE-CD and AE-CC groups. AE-Con mice had increased systemic and retinal oxidative stress compared with WT-Con animals. Vitamins C and E and the multivitamin-mineral complex reduced oxidative stress and ultrastructural retinal changes in this murine model of hypercholesterolemia.