Neuroprotective properties of estrogen have been established in animal models, but clinical trials of hormone replacement therapy (HRT) produced contradictory results. We examined the impact of HRT on age-related regional changes in human brain volume. Six brain regions were measured twice, five years apart, in 12 healthy women who took HRT and in matched controls who did not. The controls showed a typical pattern of differential brain shrinkage in the association cortices and the hippocampus with no change in the primary visual cortex. In contrast, women who took HRT showed comparable shrinkage of the hippocampus but no significant shrinkage of the neocortex. Future large scale studies may benefit from applying regional rather than global measures in assessment of brain integrity.