Several lines of evidence suggest that 17β-estradiol (βE2) has neuroprotective properties. The risk and severity of dementia are decreased in women who have received estrogen therapy, and βE2 protects neurons in vitro against death from a variety of stressors. Neuroprotection by βE2 has been suggested to be due to free radical scavenging. We demonstrate an additional neuroprotective mechanism whereby βE2 protects against NMDA-induced neuronal death by directly inhibiting the NMDA receptor.