The cardiovascular benefits of fish-derived long-chain polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid are well established. Less studied are specific effects of individual long-chain polyunsaturated fatty acids. Based on data from 16 published clinical trials, this review examines effects of DHA triglyceride (TG) oil derived from algae (algal-DHA) on serum TG levels and related parameters. Study populations included subjects with both normal and elevated TG levels including those with persistent hypertriglyceridemia treated with concomitant 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. At doses of 1-2 g/d, algal-DHA significantly lowered plasma TG levels (up to 26%) either administered alone or in combination with statins. The reduction in TG levels was markedly greater in hypertriglyceridemic than in normal subjects. Algal-DHA modestly increased plasma levels of both high-density lipoprotein and low-density lipoprotein cholesterol. The increased plasma level of low-density lipoprotein cholesterol was associated with a shift of lipoprotein particle size toward larger, less atherogenic subfractions. In some subjects, blood pressure and heart rate were significantly reduced. Algal-DHA was safe and well tolerated. Unlike fish oil, algal-DHA seldom caused gastrointestinal complaints such as fishy taste and eructation, attributes of importance for patient compliance in high-dose therapy. Regression analysis that showed a linear relationship between baseline TG and magnitude of TG reduction suggests that a study of patients with very high TG levels (>500 mg/dL) is warranted. Future pharmacologic therapies for treating hypertriglyceridemia may include algal-DHA.