Gonadal or exogenous estradiol is neuroprotective in multiple experimental paradigms. The role exerted by endogenous extragonadal estradiol synthesis in neuroprotection, however, is poorly understood. Here we show that a dose of kainic acid (3 mg/kg body weight) that does not produce detectable neuronal damage in control male and female gonadectomized rats induces a significant loss of hippocampal hilar neurons after the systemic inhibition of aromatase, the enzyme involved in estradiol biosynthesis from androgens. Extragonadal aromatase inhibition exerts a similar neuronal loss in both male and female rats (26% and 30% reduction in the number of hilar neurons, respectively). These findings indicate that extragonadal estradiol exerts a neuroprotective effect in both sexes, which prevents neuronal loss as a consequence of mild neurodegenerative signals.