We investigated the effects of purified eicosapentaenoic acid (EPA) ethyl ester capsules (90% purity), which are free from cholesterol, saturated fatty acids and docosahexaenoic acid (DHA), on plasma lipoproteins and cholesteryl ester transfer protein (CETP) activity. We administered 2.7 g of EPA per day as capsules for 6 months to 14 primary hypercholesterolemic subjects. Total cholesterol, triglyceride and low density lipoprotein (LDL)-cholesterol levels in plasma were significantly reduced. The LDL cholesterol/apoB ratio and LDL particle size did not change. The ratio of high density lipoprotein (HDL)2/HDL3 cholesterol increased from 1.04 to 1.35 (p < 0.05), while the HDL cholesterol level did not change. CETP activity was significantly reduced. The reduction of CETP activity may explain the increase in the HDL2/HDL3 cholesterol ratio. These results suggest that purified EPA not only reduces LDL cholesterol levels but also acts on HDL metabolism in patients with hypercholesterolemia and therefore will be useful for the treatment of hypercholesterolemia.