Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective degeneration of motor neurons and glial activation. Cell-specific transcriptional regulation induced by oxidative stress may contribute to the survival and activation of astrocytes in the face of motor neuron death. In the present study, we demonstrate an age-dependent increase in Bcl-xL and Ets-2 immunoreactivity that correlates with an increase of glial fibrillary acidic protein (GFAP)-positive cells in the ventral horn of the spinal cord in both ALS transgenic mice [mutant SOD1 (G93A)] and affected humans. Chromatin immunoprecipitation (ChIP) analysis verified that Ets-2 preferentially occupies the Ets-2 binding element in the promoter of Bcl-xL in primary astrocytes under oxidative stress conditions as well as in G93A spinal cords. Ets-2 small-interfering RNA down-regulated the transcriptional activity of Bcl-xL. In primary glial cultures, Bcl-xL overexpression and mutant SOD1 (G93A) both conferred resistance to oxidative stress-induced cell death. Our findings suggest that Ets-2 transcription factor activation of Bcl-xL gene may protect glia from constitutive oxidative stress that is thought to be a key mechanism contributing to the pathogenesis of ALS. This survival pathway may contribute to the glial survival and activation seen in the spinal cord of ALS patients.—Lee, J., Kannagi, M., Ferrante, R. J., Kowall, N. W., Ryu, H. Activation of Ets-2 by oxidative stress induces Bcl-xL expression and accounts for glial survival in amyotrophic lateral sclerosis.