The pathogenesis of de novo glioblastoma multiforme (GBM) is poorly understood and precursor cells are not known. To gain insight into the pathogenesis of GBM we analyzed brains from primates that developed de novo tumors ten years after whole brain radiation. Four animals had clinical and radiological evidence of GBM, and two animals had no evidence of GBM at the time of euthanization. Tumor precursor cells were identified diffusely scattered in the grossly normal white matter of all animals including two monkeys without evidence of GBM by MR-imaging or on autopsy examination. Tumor precursors demonstrated cellular atypia and mitoses, and were negative for tumor-associated markers GFAP, EGFR and p53. The cells were positive for Ki67 and N-CoR, the nuclear corepressor of astroglial differentiation. These results suggest that radiation-induced nuclear damage to neural stem cells or early astrocytic precursor cells can prevent normal differentiation and lead to tumor development. The findings provide insight into the tumorigenesis of de novo GBMs and suggest a new strategy for treatment of these lethal tumors by targeting both inactivation of N-CoR and inhibition of EGFR.