OBJECTIVE: Although previous research has shown that initiation of postmenopausal estrogen hormone therapy (HT) in late life increases risk of dementia, animal studies and some observational studies have suggested that midlife use of HT may be beneficial; however, this has not been rigorously investigated in large population-based studies. Our objective was to compare HT use in midlife with that in late life on risk of dementia among 5,504 postmenopausal female members of an integrated healthcare delivery system. METHODS: HT use was determined at midlife (mean age, 48.7 years) from a survey in 1964 and in late life (mean age, 76 years) using pharmacy databases from 1994 to 1998. Risk of dementia diagnosis was evaluated with inpatient and outpatient diagnoses made in Neurology, Neuropsychology, and Internal Medicine from 1999 to 2008. Cox proportional hazard models were used to examine effects of HT use at different times on dementia risk with adjustment for age, education, race, body mass index, number of children, and comorbidities. RESULTS: A total of 1,524 women (27%) were diagnosed with dementia during the follow-up period. Compared to women never on HT, those taking HT only at midlife had a 26% decreased risk (multivariate adjusted hazards ratio [aHR], 0.74; 95% confidence interval [CI], 0.58-0.94 ), whereas those taking HT only in late life had a 48% increased risk (aHR, 1.48; 95% CI, 1.10-1.98), and women taking HT at both mid and late life had a similar risk of dementia (aHR, 1.02; 95% CI, 0.78-1.34 ). INTERPRETATION: These findings suggest that use of HT in midlife only may protect against cognitive impairment, whereas HT initiation in late life could have deleterious effects.