The effect of estrogen on smooth muscle in various organs is unpredictable. Little is known about the effect of estrogen on respiratory tract smooth muscle, particularly in humans. In the present study we used the histamine challenge test (HCT) to assess the effect of estrogen replacement therapy (ERT) on airway reactivity in postmenopausal women who did not suffer from respiratory disease. Thirty-six women who were undergoing treatment at the postmenopausal clinic completed the study. All participants were nonsmokers whose pulmonary function tests were normal. HCT was performed twice before the inception of ERT, and a third time 4-6 weeks after ERT was begun. None of the 36 women demonstrated a 20% decrease in FEV1 values (PC20) after inhaling histamine at a concentration of 8 mg/ml, either before or during ERT. The maximal decrease in FEV1 values in response to the maximum concentration of histamine was significantly lower during ERT compared to the pretreatment period. The average maximal decrease in FEV1 during ERT was 2.63 ± 2.72% (mean ± DS) compared to 5.21 ± 4.47% and 6.57 ± 5.28% on the 2 tests prior to therapy (p < 0.0002). We conclude that ERT has an inhibitory effect on the bronchial reactivity of respiratory smooth muscle. There is no cause for concern about increased airway reactivity as an adverse effect of this ther