Dietary polyunsaturated fatty acids (PUFAs) have been reported as a potential group of natural products which modulate tumor cell growth. In present study, eicosapentaenoic acid (EPA) was found to inhibit proliferation of human leukemic HL-60 and K-562 cells in vitro. EPA arrested cell cycle progression at G0/G1 phase, and induced necrosis in both HL-60 and K-562 cells. However, EPA induced apoptosis only in HL-60 but not K-562 cells. Also, bcl-2 protein expression was downregulated in much greater extent than that of bax showing that depression of bcl-2 might be an important step during the EPA-induced apoptosis in HL-60 cells.