Neuroprotective effects of estrogen have been demonstrated against a variety of cytotoxic insults. We present data here addressing a possible mechanism of estrogen neuroprotection in the human teratocarcinoma cell line NT2 terminally differentiated to a neuronal phenotype. Cell death induced by H2O2 or glutamate results in a dose-dependent cell death of NT2 neurons, while 24 h of estrogen pretreatment significantly enhances neuronal viability. Bcl-2 expression has been shown to reduce oxidative stress and prevent cell death. In NT2 neurons, Bcl-2 levels are dramatically elevated upon differentiation and are further enhanced with estrogen treatment. These results suggest that neuroprotective effects of estrogen may be related to increases in Bcl-2 expression.