Data on the effect of hormone replacement therapy on hemostasis are inconsistent, and there are few data in women with coronary artery disease. In a single-center, open, randomized study, 118 postmenopausal women with angiographically verified coronary artery disease were randomized to hormone replacement therapy, given as long-cycle transdermal 17-beta-estradiol (50 microg/24 hour) for 3 months with sequential medroxy-progesterone acetate for 14 days, or to a control group receiving no therapy. Hemostatic parameters were measured at baseline and after 3 and 12 months of therapy. The coagulation inhibitors antithrombin, protein C, and protein S, but not tissue factor pathway inhibitor, decreased significantly from baseline in the hormone replacement therapy group at both 3 and 12 months as compared with the control group. The absolute decreases within the hormone replacement therapy group were 3 to 10%. No significant differences between the two treatment groups were observed for the coagulation products prothrombin fragment 1+2 or thrombin-antithrombin complex or for D-dimer, although there were significant decreases in the levels within the hormone replacement therapy group. Levels of fibrinogen, activated factor VII, and factor VII antigen were not significantly influenced by hormone replacement therapy treatment. Similarly, nonsignificant changes were detected for the fibrinolytic parameters tissue plasminogen activator activity, tissue plasminogen activator antigen, and global fibrinolytic activity, but plasminogen activator inhibitor type 1 was significantly lower in the hormone replacement therapy group due to a questionable increase in the levels in the control group. In conclusion, treatment with transdermal estradiol combined with long-cycle progestins was associated with no net activation of coagulation despite reduced levels of coagulation inhibitors.