BACKGROUND Many experimental and observational studies have suggested that hormone replacement therapy (HRT) in postmenopausal women is cardioprotective. However, the results of randomized controlled trials have been discouraging. We attempted to evaluate the influence of overweight, a frequent risk factor for coronary artery disease, on the lipid-modifying effects of HRT. METHODS A total of 345 postmenopausal women were divided into 2 groups according to body mass index (BMI): the control group; BMI <25 Kg/m2 (n=248) and the overweight group; BMI > or =25 Kg/m2 (n=97). All women received either 0.625 mg conjugated equine estrogen (CEE)(n=139), CEE plus 5 mg medroxyprogesterone acetate (MPA)(n=97) or CEE plus 10 mg MPA (n=109). Lipid profiles were measured before and 12 months after HRT. RESULTS In both the control and overweight groups, HRT reduced low density lipoprotein cholesterol (LDL-C) (p = 0.000 and p = 0.000 respectively) and lipoprotein (a) [Lp(a)] levels (p = 0.000 and p = 0.000 respectively) and raised high density lipoprotein cholesterol (HDL-C) levels (p = 0.000 and p = 0.002 respectively). However, the elevation of the HDL-C level was higher in the control group than in overweight group (17.5% vs. 10.4%, p = 0.015), and this was significant after adjusting for changes in body weights (p = 0.016). There were no differences in the reduction of LDL-C (p = 0.20) and Lp(a) (p = 0.09) levels between the two groups. CONCLUSIONS HRT had less favorable effects on HDL-C levels in overweight postmenopausal women than in women with normal body weight. This finding may be partially associated with no cardioprotective effect of HRT in postmenopausal patients at a high risk due to multiple risk factors including obesity.