Recent randomized clinical studies failed to show cardiovascular protection with postmenopausal hormone therapy (HT), instead raising widespread concerns about possible increased cardiovascular risk. However, these studies primarily assessed the combination of conjugated equine estrogen and medroxyprogesterone acetate, which is suspected to abolish the beneficial effects of estrogen on the microcirculation. This preliminary study evaluated the effects of HT combining 17beta-estradiol (E2) with a new progestin, drospirenone, on myocardial perfusion reserve, a surrogate marker of coronary function. In this double-blind randomized study, 56 postmenopausal women with angina pectoris received oral E2 1 mg plus drospirenone 2 mg or placebo for 6 weeks. Myocardial perfusion reserve was measured using radioactive oxygen-labeled water and positron emission tomography before and after therapy. Myocardial perfusion reserve increased significantly in the E2-drospirenone group after 6 weeks versus placebo (p<0.0008). Mean myocardial perfusion reserve increased from 4.83 at baseline to 5.13 after 6 weeks in the E2-drospirenone group (n=27), but decreased from 4.84 to 4.13 in the placebo group (n=29). No significant side effects were observed with E2-drospirenone. A larger trial is needed to investigate whether myocardial perfusion improvements will be sustained and translate into a clinical benefit in postmenopausal women at risk of coronary heart disease. In conclusion, E2-drospirenone HT for 6 weeks has favorable effects on myocardial function in postmenopausal women with angina pectoris. These data suggest that drospirenone has the desired progestin actions on the endometrium, but does not abolish the beneficial effects of estradiol on cardiac microcirculation.