Estrogen has beneficial effects on markers of coronary heart disease (CHD) risk, but may increase overall CHD events. The effects of hormone therapy on vascular endothelial function have been mixed, and require further assessment. We studied the myocardial blood flow (MBF) response to postmenopausal combination hormone therapy (CHT) in postmenopausal women with risk factors for CHD. We performed dynamic [(13)N] ammonia positron emission tomography in 15 postmenopausal women in a 7-month placebo-controlled crossover trial of continuous conjugated equine estrogen/cyclical micronized progesterone. MBF was measured at rest, after sympathetic stimulation with the cold pressor test (CPT), and after iv adenosine infusion, to determine baseline, endothelium-dependent, and maximal flows, respectively. Response to CPT was neutral in all women at baseline (- 0.51 +/- 27%). Adenosine induced a marked increase in MBF ( 161 +/- 111%). Treatment with 3 months of combined estrogen/ progestin CHT did not change CPT or adenosine MBF responses. Myocardial flow reserve was unchanged as well. In this group of postmenopausal women at higher cardiovascular risk, no association was found between CHT assignment and change in MBF. Further study is needed to clarify the effects of CHT on the endothelium of women with presumably diseased vasculature.