Objective: To study the effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity. Design: Prospective, randomized, controlled study. Setting: Academic hospital. Patient(s): Healthy postmenopausal women with an intact uterus. Intervention(s): For the first 12 months, the hormone replacement therapy group (n = 14) received oral E2, 1 mg daily, sequentially combined with 5 or 10 mg of dydrogesterone. Thereafter, they received oral E2, 2 mg daily, sequentially combined with 10 mg of dydrogesterone. The control group (n = 13) received no treatment. Data were collected at baseline and at 3, 12, and 15 months. Main Outcome Measure(s): Parameters of endothelial function and inflammatory activity. Result(s): During 12 months of follow-up, we observed decreases of 15% in plasma levels of endothelin-1, of 21% in soluble thrombomodulin, of 14% in von Willebrand factor, and of 12% in clottable fibrinogen in the hormone replacement therapy group compared with the control group. There was a 5% decrease in soluble E-selectin levels. All significant changes were observed by 3 months and sustained after 15 months. Brachial artery flow-mediated vasodilatation and C-reactive protein levels did not change significantly. Conclusion(s): Long-term combined hormone replacement therapy with E2 and dydrogesterone in healthy women was associated with sustained improvement in some aspects of endothelial function and in clottable fibrinogen levels.