Many studies have reported proliferative, differentiating or protective effects of estradiol, notably through estrogen receptor alpha (ERa). On the contrary, the ligand-independent action of ERa is currently poorly documented notably in cell protection. The stable transfection of wild type, substituted or truncated form of ERa in PC12 cells (ERa negative cell line) lead the specific study of its ligand-independent action. Hence, we demonstrate here that, in the absence of E2, the expression of ERa prevents cells from apoptosis induced by serum deprivation. This protection is not due to an ERE-mediated transcription and does not require either AF-1 or AF-2 transactivation functions. It is afforded to the Y537 residue of ERa and activation of c-Src/Stat3 signaling pathway.