Objectives: The purpose of this study was to determine the effect of usual-dose estrogen replacement therapy (ERT) on myocardial perfusion and myocardial perfusion reserve (MPR) (evoked by an endothelium-independent vasodilator) in healthy postmenopausal women. Postmenopausal women have a decreased myocardial perfusion reserve compared with younger women. Estrogen infusions are known to enhance endothelium-dependent vasodilation of the epicardial coronary arteries in postmenopausal women, but whether ERT also enhances endothelium-independent myocardial perfusion and perfusion reserve is unclear. Methods: In 24 healthy postmenopausal women who were not taking ERT, myocardial perfusion at rest, perfusion during the infusion of adenosine (a primarily endothelium-independent vasodilator), and MPR were determined by positronemission tomography (PET) and oxygen 15-labeled water. The women were then randomly assigned in a double-blind fashion to receive either 0.625 mg of oral conjugated estrogens (Premarin) or placebo per day for 4 to 6 weeks, after which they underwent a repeat cardiac PET study. Results: There was no statistical difference between those assigned to ERT and those assigned to placebo in the measurement of myocardial perfusion at rest (1.21 ± 0.31 vs 1.16 ± 0.18 mL/g/min, respectively) in response to adenosine (2.66 ± 0.96 vs 3.3 ± 0.45 mL/g/min) or MPR (2.24 ± 0.83 vs 2.88 ± 0.64 mL/g/min) after 4 to 6 weeks of oral ERT. There was also no difference between the groups in any of the myocardial perfusion measurements after correction for the rate-pressure product. Conclusions: Short-term oral ERT does not affect myocardial perfusion at rest in response to adenosine or MPR in healthy postmenopausal women. Thus potential beneficial effects of ERT on vasomotor function may be limited to enhancement of endothelium-dependent vasodilative mechanisms affecting conduit vessels.