n-3 Fatty acids (FAs) when used in doses of 3-4 g/d eicosapentaenoic acid and docosahexaenoic acid have profound effects on triacylglycerol (TG) concentrations. The mechanism for their TG reduction relates to their favorable effects on reducing hepatic production and secretion of VLDL and VLDL apolipoprotein B particles, along with favorable effects on plasma lipolytic activity through lipoprotein lipase-mediated clearance, as well as stimulation of beta-oxidation of other FAs in the liver. Their hypotriglyceridemic properties are related to both the dose of n-3 FAs used and the baseline TG concentrations of the population. In patients with TG concentrations >500 mg/dL, 4 g n-3 FAs have been shown to reduce TGs by 45%, VLDL by 42%, and non-HDL by 10.2%. A recent pooled meta-analysis with multiple doses of n-3 FAs ranging from 0.8 to 5.4 g revealed changes in TGs of -27 mg/dL (95% CI: -33, -20), in HDL of +1.6 mg/dL (95% CI: + 0.8, +2.3), and in LDL cholesterol of +6 mg/dL (95% CI: + 3, +8). The clinical uses of n-3 FAs include treatment of severe and moderate hypertriglyceridemia, use in statin-treated patients with elevated TG concentrations or non-HDL cholesterol (mixed hyperlipidemia), and use in the secondary and primary prevention of cardiovascular disease. Existing large-scale clinical trials such as the GISSI-Prevenzione Study and JELIS with low doses of n-3 FAs (1-2 g) show clinical benefit in reducing coronary heart disease without substantial changes in concentrations of TGs or other lipids. Future clinical trials need to determine whether the TG-lowering doses of n-3 FAs (3-4 g/d) result in additional risk reduction.