Late effects after radiotherapy for brain tumors can be severe and tend to limit the efficacy of this treatment modality. The mechanisms governing the development of late radiation-induced lesions in the brain are not clear, but they are preceded by cycles of molecular and cellular events including production of cytokines, one of which is tumor necrosis factor (TNF)-alpha. There is literature to support possible roles for TNF-alpha as a contributor to edema, gliosis, and demyelination in the brain, all of which are histopathologically associated with radiation-induced brain damage. We have examined the role of TNF-alpha signaling in the response to brain irradiation using TNFRp55- or TNFRp75-deficient and control mice. Mice lacking TNFRp75 exhibited increased early radiation-induced apoptosis in putative stem cell regions of the brain. At 1 month, they had decreased proliferative responses in the same regions, and by 3 months they were demonstrating dose-dependent seizures and other severe neurological abnormalities that were not seen in control or TNFRp55-/- mice. Seizure activity correlated with the onset of extensive demyelination, and by 6 months, levels of myelin basic protein in irradiated TNFRp75-/- mice were approximately 40% of those seen in the other two strains; the animals were moribund and had to be euthanized. These observations indicate that radiation-induced TNF-alpha, acting through TNFRp75, protects against the development of late complications of brain irradiation.