We determined if the apolipoprotein E(APO E) genotype affects the exercise training-induced increase in plasma high-density lipoprotein cholesterol (HDL-C) and HDL2-C. Sedentary overweight men on an American Heart Association (AHA) step I diet had plasma lipoprotein-lipids measured before and after 9 months of endurance exercise training. APO E2 (n = 6), E3 (n = 33), and E4 (n = 12) groups were similar at baseline in terms of age, body weight and composition, and plasma lipoprotein-lipid profiles. APO E2 men had a larger increase in plasma HDL-C and HDL2-C with exercise training than APO E3 and E4 men (HDL-C, 8 ± 4 v 3 ± 1 v 2 ± 1 mg/dL; HDL2-C, 5 ± 3 v 1 ± 1 v - 1 ± 1 mg/dL; mean ± SE, all P < .01). After adjusting for body weight changes, the increases in plasma HDL-C and HDL2-C remained greater in APO E2 versus E3 and E4 men (all P < .03). These results indicate that APO E2 men may have greater plasma HDL-C and HDL2-C increases with endurance exercise training.