Traditional approaches to prophylaxis of atherosclerosis have focused on one aspect of the pathogenesis of this multifactorial disease, such as platelet function or blood lipids, and therefore have had limited success. Epidemiologic studies show a striking inverse correlation of consumption of fish rich in the two omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, and mortality from cardiovascular disease. In studies of volunteers and patients, reductions in platelet responsiveness, lowering of blood lipids, and improvements of blood flow, as well as improvements in other values implicated in the pathogenesis of atherosclerosis, were induced with eicosapentaenoic and docosahexaenoic acids. These findings indicate that these omega-3 fatty acids have a larger prophylactic potential than traditional approaches. This potential must be scrutinized in meticulously designed and conducted trials with clinical endpoints.