In the 80's, retrospective studies showed an inverse relation between fish consumption and ischemic heart disease (IHD) mortality. In parallel, fish fats containing the polyunsaturated fatty acid (PUFA) eicosapentaenoic (EPA) were shown to impair platelet aggregation and thromboxane formation. The results of the large prospective trials, the Diet and Reinfarction Trial (DART) and the Lyon Heart Study in the secondary prevention of myocardial infarction, have further supported the interrelationships between diet and dietary prevention of IHD. In the DART Study, the cardioprotection by EPA was paralleled by an increase plasma content of EPA. In the Lyon, in addition to changes in the content of EPA, changes in other well known variables (i.e. leukocytes and vitamin E), often abnormal in subjects prone to arterial thrombosis, have been found. The GISSI Prevenzione Trial was a prospective, multicentric, open labeled trial with a factorial design, in which 11,324 recent (<3 mo) survivors of a first myocardial infarction were assigned to receive, in addition to the usual strategy, a supplementation of n-3 PUFA, vitamin E, or the combination of the two. Cardiovascular death (-30%), coronary heart disease death (-35%), total death (-20%) and sudden death (-45%) were all significantly reduced by the n-3 PUFA supplementation. The reduced tendency to sudden death of survivors of myocardial infarction on treatment with n-3 PUFA are in keeping with a series of scanty but reliable clinical data as well as of experimental studies. However, we believe that large-scale prospective multicentric randomized trials aimed at preventing sudden death in high-risk patients as well as at testing the effects of n-3 PUFA in patients with intracoronary devices and sustained ventricular arrhythmias, are a major direction to be followed to better understand the n-3 PUFA and sudden death issue.