Estradiol at physiological concentrations intervenes in apoptotic death cascades and ameliorates neuronal death in experimental models of focal and global ischemia. The cellular targets that mediate estradiol protection of hippocampal neurons in global ischemia are, however, unclear. The present study examined the hypothesis that estradiol protects hippocampal neurons in ovariectomized rats via estrogen receptor (ER)α and/or β. Estradiol (14 d pretreatment) afforded robust protection of CA1 neurons against global ischemia-induced death. The broad-spectrum ER antagonist ICI 182,780 (intracerebroventricularly, 0 and 12 h after ischemia) abolished estrogen protection, consistent with a role for ERs. To evaluate the potential roles of ERα vs. ERβ in estrogen protection, we administered subtype-selective agonists for 14 d before and 7 d after ischemia. The ERα-selective agonist propyl pyrazole triol (PPT, 10 mg/kg) and ERβ-selective agonist WAY 200070–3 (1 mg/kg) produced nearly complete protection of CA1 neurons in approximately 50% of the animals. PPT, but not WAY 200070–3, at doses used for protection, elicited lordosis, induced negative feedback inhibition of LH release, and reduced weight gain. These findings establish the efficacy of the PPT dose in neuroendocrine assays and specificity of WAY 200070–3 for ERβ. We also examined the ability of estradiol and neuronal injury to regulate ERα and ERβ expression. Both estradiol and global ischemia markedly increased ERα, but not ERβ, protein in CA1. These data indicate that estradiol can act via ERα and ERβ to protect CA1 neurons from global ischemia-induced death and that both estradiol and global ischemia modulate ERα expression in hippocampal CA1.