Supplements and diets enriched in antioxidants and soy isoflavones are purported to reduce cardiovascular disease risk. Many experimental studies have demonstrated inhibitory effects of antioxidants and soy isoflavones on the development of fatty streaks in animal models. However, it is still unknown whether antioxidants and isoflavones have comparable inhibitory effects on the progression of advanced stages of atherosclerosis. This is an important question because clinical trials in humans have not supported a cardio-protective role for antioxidants or isoflavones. Thus, we examined the effects of antioxidants and genistein on the progression and composition of established, advanced atherosclerotic lesions in the innominate arteries (IA) of older apolipoprotein E-deficient (apoE(-/-)) mice. Thirty-week-old male apoE(-/-) mice were fed chow with or without genistein (0.27%, w/w) for 6, 12 and 24 weeks. Twenty-week-old male apoE(-/-) mice were fed chow with or without a cocktail of antioxidants (vitamin E 0.2%, w/w; vitamin C 0.05%, w/w; and beta carotene 0.5%, w/w) for 10, 16, and 22 weeks. There were no significant differences in total plasma cholesterol, body weight, average lesion or medial area, or changes in lesion composition with either treatment in comparison to control mice.