We prospectively evaluated the association of hormone replacement therapy and asthma incidence in a cohort of pre- and postmenopausal women 34 to 68 yr of age. During 582, 135 person-years of follow-up between 1980 and 1990, 726 new cases of asthma were documented. Postmenopausal women who were never users of replacement hormones had a significantly lower age-adjusted risk of asthma than premenopausal women (relative risk = 0.65; 95% confidence interval [CI] = 0.46 to 0.92). Among naturally menopausal women, the age-adjusted relative risk of asthma for ever use of postmenopausal hormones was 1.49 (95% CI = 1.10 to 2.00); for current use of hormones (conjugated estrogens with or without progesterone), 1.50 (95% CI = 0.98 to 2.30); and for past use, 1.52 (95% CI = 1.08 to 2.13), compared with never use of hormones. Ever users of 10 or more years' duration had twice the age-adjusted risk of asthma compared with women who never used postmenopausal hormones (95% CI = 1.39 to 2.87). Among current users of conjugated estrogens, there was a positive dose-response demonstrated between daily dose and asthma risk (p for trend = 0.007). While confirmatory studies are warranted, these data suggest that estrogen plays a role in the pathophysiology of asthma and that long-term use and/or high doses of postmenopausal hormone therapy increase subsequent risk of asthma.