Numerous studies, both in vivo and in vitro, have reported neuronal differentiating and neuroprotective actions of estrogens. Most of these estrogenic effects are mediated through specific receptors termed estrogen receptors. The aim of this study was to assess the importance of the N-terminal A/B domain of the estrogen receptor-alpha (ER alpha) in its neuronal aspects. Consequently, estrogen effects on (i) the transcriptional activity of target genes, (ii) neuronal differentiation and (iii) neuroprotection in PC12 cells transfected with either a full length form of ER alpha or an A/B domain truncated form (ER alphaCF), have been studied. We demonstrate that the maximal estrogen-induced transcriptional activity of reporter genes requires a full length ER alpha, especially when cells are differentiated. Precisely, the transcriptional activity of ER alpha in differentiated cells relies, predominantly, on the activation function AF-1, located in the A/B domain. Furthermore, in PC12 cells stably expressing ER alpha, 17beta-estradiol markedly enhances the neurite outgrowth triggered by treatment with nerve growth factor and protects cells from oxidative shocks induced by depletion of glutathione. These estrogenic effects are not observed in non-transfected cells and in cells transfected with the truncated ER, devoid of the A/B domain. Altogether, these results underline the importance of the A/B domain of ER alpha in both the differentiating and the neuroprotective effects of estrogens.