Omega-3 fatty acid therapy shows great promise in the secondary prevention of coronary artery disease. A meta-analysis of recent omega-3 trials shows reductions of coronary heart disease mortality of 36% (95% CI, 20%-50%; P<0.001) and total mortality of 17% (95% CI, 0%-32%; P=0.046). Some of the potential mechanisms for cardiovascular protection include a reduction in cardiac arrhythmias and plaque stabilization. Since the publication of the landmark GISSI-Prevenzione trial, there have been three major intermediate cardiovascular endpoint studies in patients with implantable cardioverter defibrillators (ICDs) and one large trial, the Japan EPA Lipid Interventional Study (JELIS) trial, which involved 18,645 Japanese patients in primary and secondary prevention. The three studies with ICD patients have been mixed, with favorable trends toward reduction in the incidence of ventricular arrhythmias in some but not all of the studies. Results of the recent JELIS trial in a Japanese population already consuming a high intake of omega-3 fatty acids showed a 19% risk reduction in major coronary events. Most of the reductions were in unstable angina and nonfatal coronary events, but not in sudden death and cardiovascular mortality. The totality of evidence suggests greater benefits with omega-3 fatty acids in secondary prevention than primary prevention and in populations consuming low amounts of omega-3 fatty acids.