Recent findings indicate that estrogen is neuroprotective, a cellular effect that may contribute to its clinical benefits in delaying the development of Alzheimer's disease. In this report, we identify a novel neuronal action of estrogen that may contribute to its neuroprotective mechanism(s). Specifically, we report that estrogen significantly increases the expression of the anti-apoptotic protein Bcl-xL in cultured hippocampal neurons. This effect presumably reflects classic estrogen transcriptional regulation, as we identified a putative estrogen response element in the bcl-x gene. Estrogen-induced enhancement of Bcl-xL is associated with a reduction in measures of β-amyloid-induced apoptosis, including inhibition of both caspase-mediated proteolysis and neurotoxicity. A similar relationship between estrogen, Bcl-xL expression, and resistance to degeneration was also observed in human hippocampus. We report neuronal colocalization of estrogen receptor and Bcl-xL immunoreactivities that is most prominent in hippocampal subfield CA3, a region that shows relatively little immunoreactivity to paired helical filament-1, a marker of Alzheimer's disease neurodegeneration. These data suggest a novel mechanism of estrogen neuroprotection that may be relevant to estrogen's suggested ability to modulate neuronal viability across the life span, from neural sexual differentiation and development through age-related neurodegenerative conditions.