Glia maturation factor (GMF) is a highly conserved protein found mainly in the nervous system. The current work was undertaken to investigate the effect of GMF expression in astrocytes on CuZn superoxide dismutase (CuZnSOD or SOD I) and on the vulnerability of the cells to H2O2 toxicity. Primary astrocyte cultures were derived from mice in which the GMF gene was completely deleted by homologous recombination (knockout). Astocytes derived from knockout animals displayed a lower level of CuZnSOD activity and protein. The reduction in CuZnSOD was restored by transfection with a GMF/adenovirus construct, and the resulting increase was blocked by the p38 MAP kinase inhibitor SB203580. There was no change in the other isoform of SOD (MnSOD or SOD II). Endogenous H2O2 was lower in the knockout cells, and the cells became more resistant to H2O2 toxicity compared to the wild type. In the GMF-null cells, concurrent with a decrease in CuZnSOD, the function of which is to convert superoxide to H2O2, there was an increase in the activity of the two enzymes that degrade H2O2: catalase and glutathione peroxidase. By regulating the redox state of the cell, GMF may be involved in a wide spectrum of cellular events ranging from survival, proliferation, differentiation, to death.