OBJECTIVE To study the association of estrogen-replacement therapy and other estrogen-related variables with Alzheimer's disease in postmenopausal women. BACKGROUND Postmenopausal estrogen use has been reported to lower the risk of Alzheimer's disease. METHODS A population-based, multicenter survey was carried out in eight Italian municipalities. The sample of 2,816 women, aged 65 to 84 years, was randomly selected from the population register of each municipality and stratified in 5-year age groups. All women were screened using the Mini-Mental State Examination and interviewed concerning risk factors. Those who screened positive underwent a clinical assessment. Dementia syndrome was diagnosed according to DSM-III-R criteria, and Alzheimer's disease was diagnosed according to NINCDS-ADRDA criteria for possible and probable Alzheimer's disease. RESULTS The estimated prevalence of postmenopausal estrogen use adjusted to the 1991 Italian female population was 12.3%. The frequency of estrogen use was higher among nonpatients compared with Alzheimer's disease patients (odds ratio, 0.24; 95% confidence interval, 0.07 to 0.77). The inverse association between estrogen therapy and Alzheimer's disease remained significant after adjustment for age, education, age at menarche, age at menopause, smoking and alcohol habits, body weight at the age of 50 years, and number of children (odds ratio, 0.28; 95% confidence interval, 0.08 to 0.98). CONCLUSIONS Our data from a population-based study support the hypothesis that estrogen-replacement therapy is associated with a reduced prevalence of Alzheimer's disease in postmenopausal women. Prospective clinical trials are required to enable women and their physicians to weigh risks and benefits of estrogen-replacement therapy for the prevention of dementia.