Determining the benefits and/or drawbacks of hormone replacement therapy (HRT) on women's health is an imperative public health goal. Research in rodents suggests benefits of estrogen on neuronal growth and function. However, little research has investigated the effects of HRT on brain tissue in humans. We used high-resolution magnetic resonance imaging and an optimized voxel-based morphometric technique to examine the effects of HRT on brain volume in postmenopausal women. We report two main results: (a) HRT is associated with the sparing of grey matter in prefrontal, parietal, and temporal brain regions and white matter in medial temporal lobe regions, and (b) longer durations of therapy are associated with greater sparing of grey matter tissue. HRT should be considered a possible mediator of age-related neural decline in both grey and white matter tissues.