Objective: To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemostatic factors in postmenopausal women. Design: Twenty subjects were treated with oral E-2 valerate (2 mg) combined with cyproterone acetate (1 mg) (group I) and 21 with transdermal E-2 (1.5 mg) plus oral medroxyprogesterone acetate (5 mg) (group II). The effects on lipid profile and hemostatic parameters were evaluated at baseline and after 3, 6, and 12 months of treatment. Results: Group I showed a stronger increase of high-density lipoprotein (HDL) cholesterol levels (2-8%) and stronger reduction of atherogenic indices (total cholesterol/HDL cholesterol and low-density lipoprotein/HDL cholesterol) than group Il. Group II showed a more pronounced reduction of triglyceride (21-31%) and factor VII (6-10%) levels than group I. Both groups showed reduced concentrations of total cholesterol, low-density lipoprotein cholesterol, tissue plasminogen activator, plasminogen activator inhibitor-1, antithrombin III, and protein S, whereas protein C was increased after 12 months of treatment. Conclusions: The cardioprotective effects of hormone replacement therapy are demonstrated by favorable effects on lipid profile and fibrinolytic activity. Oral hormone replacement therapy showed a more prominent effect on lipoprotein metabolism than did transdermal administration, but transdermal medication had a stronger effect on triglyceride and coagulation factors. However, it needs to be considered that there is an increased risk of venous thrombotic events in the first year of treatment.