Population studies indicate omega-3 that a high fish intake, such as reported in the early Eskimo and Japanese studies, is associated with a low mortality from coronary heart disease (CHD). These effects have been associated with measurable effects on a series of established and possible risk factors. In most of the later population studies much lower daily intake of fish has been observed, such intake having only small or not even measurable effects on established risk factors. Still, their association with reduced CHD mortality, particularly sudden cardiac death seem to be reasonably well established. Beneficial effects are found at a level of consumption of about 30 g per day or 1 fish meal per week compared with populations rarely or never consuming fish. Such findings are also reflected in studies including analysis of fatty acid composition in adipose tissue and cell membranes. Fish consumption may be a marker for a healthier lifestyle or, alternatively, fish consumers may be at higher self-perceived risk for CHD and are therefore eating fish to reduce their high baseline risk. Despite all these limitations, the population studies seem to indicate that a high fish intake is associated with a low mortality from CHD. GISSI-Prevenzione was conceived as a population, pragmatic trial on patients with recent myocardial infarction and it was conducted in the framework of the Italian public health system. In GISSI-Prevenzione, 11,323 patients were enrolled in a clinical trial aimed at testing the effectiveness of omega-3 PUFA and vitamin E. Patients were invited to follow Mediterranean dietary habits, and were treated with up-to-date preventive pharmacological interventions. Long-term omega-3 PUFA 1 g daily, but not vitamin E 300 mg daily, was beneficial for death and for combined death, non-fatal myocardial infarction, and stroke. All the benefit, however, was attributable to the decrease in risk for overall, cardiovascular, cardiac, coronary, and sudden death. In GISSI-Prevenzione, long-term administration of omega-3 PUFA (1 g daily) significantly decreased the risk of overall (-20%), cardiovascular (-30%), and sudden death (-45%). At variance from the orientation of a scientific scenario largely dominated by the "cholesterol-heart hypothesis", GISSI-Prevenzione results indicate omega-3 PUFA (virtually devoid of any cholesterol-lowering effect) as a relevant pharmacological treatment for secondary prevention after myocardial infarction.