Clinical and experimental evidence suggests that the cardioprotective effect of estrogen replacement is due to effects both on scrum lipids and on blood vessels. Current practice includes the use of a progestin in combination with estrogen if the patient still has her uterus: however, little is known about the effects of combination therapy on vascular reactivity. We therefore studied the effects of estrogen alone and with added progestin on forearm vascular resistance at rest, during reactive hyperemia, and after cold pressor stimulation using plethysmography in six healthy, postmenopausal women. Measurements were made before therapy: after giving conjugated estrogen i.v.; followed by a daily oral dose of 0.625 mg for 21 days; and sequentially after the addition of 10 mg of medroxyprogesterone acetate (MPA) for 10 days. Mean blood pressure did not change significantly. After 21 days of estrogen therapy, forearm blood flow, resting vascular resistance, and resistance after cold pressor stimulation did not change significantly. However, after addition of MPA, resting forearm vascular resistance rose significantly from baseline: 25.7 ± 2.7 U (SE) versus 38.3 ± 2.5 (p = 0.004). In addition, forearm vascular resistance rose to a higher level after cold pressor stimulus during combination therapy (32.3 ± 5.9 vs. 58.4 ± 5.7; p = 0.0057) than after estrogen replacement alone (32.3 ± 5.9 vs. 37.7 ± 5.3; p = NS). We conclude that combination hormone replacement therapy results in higher resting vascular resistance and increased pressor responsiveness than does estrogen replacement therapy alone.