Oligodendrocytes and subependymal cells in the adult CNS have been shown to undergo radiation-induced apoptosis. Here, we examined the role of p53 in radiation-induced apoptosis in the adult mouse CNS. In the spinal cord of p53+/+ mice, apoptotic glial cells were observed within 24 h after irradiation, and the apoptotic response peaked at 8 h. These apoptotic cells demonstrated the immunohistochemical phenotype of oligodendrocytes, and decreased oligodendrocyte density was observed at 24 h after 22 Gy. A similar time course of radiation-induced apoptosis was seen in subependymal cells in the adult mouse brain. Radiation-induced apoptosis was preceded by an increase in nuclear p53 expression in glial cells of the spinal cord and subependymal cells of the brain. There was no evidence of radiation-induced apoptosis in the spinal cord and subependymal region of p537/7 animals. We conclude that the p53 pathway may be a mechanism through which DNA damage induces apoptosis in the adult CNS. Cell Death and Differentiation (2000) 7, 712 ± 720.