Residual risk, which cannot be prevented by statins alone, must be controlled for inhibiting the onset of coronary events. Omega-3 polyunsaturated fatty acids (PUFAs) play an important role in controlling residual risk. The Japan eicosapentaenoic acid (EPA) Lipid Intervention Study demonstrated the inhibitory effect of high-purity EPA preparations on the residual risk of cardiovascular events. Omega-3 PUFAs inhibit coronary artery disease (CAD) through various actions, including triglyceride-lowering action. Besides lipid metabolism, platelet aggregation inhibition, anti-inflammatory effects, improved vascular endothelium function, and anti-hypertensive action contribute to arteriosclerosis inhibition. Conversely, several recent studies did not demonstrate the efficacy of omega-3 PUFAs for CAD prevention. PUFAs levels may need to exceed a threshold for anti-arteriosclerotic action. The efficacy of EPA might depend on the baseline value of the EPA/arachidonic acid (AA) ratio prior to EPA administration. This baseline EPA/AA ratio value varies according to country and region as well as changes of dietary habits. More global research in this field is needed to identify an optimal omega-3 PUFAs administration strategy.