Despite numerous studies showing neurotrophic and neuroprotective effects of estrogen in animal models, the long-term effects of estrogen use on brain morphology in older women are not known. Thus, we compared ventricular, cerebrospinal fluid, white matter, and grey matter volumes estimated from magnetic resonance images of postmenopausal women with more than 20 years exposure to unopposed estrogen, women who were not on estrogen, and young healthy women. Estrogen users had significantly smaller ventricles and greater white matter volumes than non-users, but hormone exposure did not affect grey matter volumes. Young healthy women had significantly smaller ventricles, less cerebrospinal fluid and more grey matter than both groups of older women. However, they had comparable white matter volumes to older women on estrogen. These findings suggest that long-term estrogen protects against white matter loss in aging. This adds to findings from other studies suggesting estrogen is neuroprotective of the hippocampus and other regions in older women.