Objective The effects of hormone replacement therapy (HRT) and tibolone can affect many aspects relevant to cardiovascular disease including vasomotor function, inflammation, and hemostasis. Recent studies have demonstrated that HRT exerts a mixture of both protective and adverse effects. In the current study, we compared the effects of HRT and tibolone on a variety of relevant cardiovascular parameters. Methods and Results This study was randomized, double-blind, placebo-controlled, crossover in design. Twenty-six postmenopausal women received placebo. Fifty-three women received micronized progesterone (MP) 100 mg with conjugated equine estrogen (CEE) 0.625 mg or tibolone 2.5 mg daily during 2 months with 2 months washout period. Placebo did not significantly change all parameters from the respectvie baseline values. Compared with HRT, tibolone significantly reduced total cholesterol (p<0.001), triglyceride (p<0.001), HDL cholesterol (p<0.001) levels, and triglyceride/HDL cholesterol ratios (p<0.001) except LDL cholesterol levels. Despite marked reductions of HDL cholesterol levels, tibolone significantly improved flow-mediated brachial artery dilator response to hyperemia from baseline values (p<0.001) by a similar magnitude to HRT (p=0.628). HRT significantly increased high sensitivity CRP (hsCRP) (p=0.030) and reduced antithrombin III (p<0.001) compared with tibolone showing no changes. HRT and tibolone significantly increased prothrombin fragment 1+2 (F1+2) from baseline values (p<0.001 and p=0.004, respectively). Of interest, the effects of HRT and tibolone on hsCRP, antithrombin III, and F1+2 were significantly different. HRT and tibolone significantly reduced plasma PAI-1 antigen levels from baseline values (p=0.006 and p=0.005, respectively) to a similar degree (p=0.988). Conclusions Compared with HRT, tibolone significantly changed lipoprotein levels. Tibolone significantly improved flow-mediated brachial artery dilator response, however, tibolone did not significantly change hsCRP and antithrombin III and tibolone decreased F1+2 less than HRT.