BACKGROUND The beneficial effect of hormone replacement therapy (HRT) on cardiovascular disease has been documented in postmenopausal women, but has a significant time trend. Thus, it is worthwhile to further study whether there are different effects on cardiovascular factors between short- and long-term use of HRT. METHODS Prospective study of the changes on lipoprotein profile, hemostatic factors, and platelet aggregation was evaluated in 21 postmenopausal women receiving oral E2 valerate (2 mg/d) combined with medroxyprogesterone acetate (10 mg/d) during the last 10 days of each 21-day cycle. The treatment period was 24 months. RESULTS During the 24 months of treatment, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and atherogenic indices- total cholesterol-to-high-density lipoprotein cholesterol (HDL-C) and LDL-C-to-HDL-C, were significantly reduced. The concentrations of tissue plasminogen activator and plasminogen activator inhibitor-1 were significantly reduced after 12 months of HRT. In addition, the concentrations of antithrombin III were significantly increased, but protein S was statistically decreased during the 18 months of HRT. The maximum aggregation and slope of platelet aggregation were significantly reduced only during the first 12 months of HRT. CONCLUSIONS This study demonstrates that there were some differences in cardiovascular risk factors between short- and long-term HRT, especially in changes in platelet aggregation and hemostatic factors. However, the long-term favorable effect on lipoprotein metabolism and fibrinolytic activity among hormone users may explain, in part, the inverse association between HRT and cardiovascular disease.