The clinical sequelae of atherosclerosis, coronary heart disease, stroke, and peripheral vascular disease are the leading causes of morbidity and mortality in the United States. A collection of "risk-factors" explains only part of the variation in atherosclerosis between individuals, suggesting that other yet to be determined factors contribute to the risk of atherosclerosis and cardiovascular disease. Several lines of evidence suggest that oxidation of lipoproteins pla)is a role in atherogenesis. Population-based studies and studies in experimental animals suggest that antioxidants reduce atherosclerosis and cardiovascular disease. Basic biochemical studies offer a number of mechanism(s) by which antioxidants might provide this protection. However, the few data from clinical trials of supplementation of the diet with isolated nutrient antioxidants do not consistently support an inhibitory role for antioxidants in atherogenesis and cardiovascular disease. Thus, appropriately designed clinical trials are needed before recommendations for dietary intake of specific antioxidants to reduce risk of atherosclerosis and cardiovascular disease can be developed Such trials should be designed based on a critical evaluation of the existing body of basic and clinical data for the inhibitory effects of antioxidants on atherogenesis. Attention should be specifically paid to the body of data showing interaction of various antioxidants. The issue of antioxidant needs for optimal prevention of atherosclerosis as a function of pathological, physiological, dietary, and behavioral characteristics of individuals should be addressed. Execution of properly designed clinical trials would be facilitated by identification of biomarker(s) that accurately reflect the extent to which art antioxidant intervention inhibits atherosclerosis. Despite uncertainty regarding the health benefits of isolated antioxidant(s), all available evidence continues to support the health benefits of increased consumption of a wide variety of fruits and vegetables rich in antioxidants.