THE role of neuronal damage in the radiation-induced CNS injury resulting from brain tumor therapy remains poorly understood. To begin to define the radioresponse of neurons, the survival of rat cortical neuron cultures was investigated. Neuronal survival was reduced by ∼40% 24–48 h after irradiation with 3.5 Gy. The addition of the free radical scavenger NAC after irradiation increased neuronal survival. Neurons were also significantly less sensitive to radiation in co-cultures with astrocytes or in the presence of astrocyte-conditioned medium. Medium conditioned on astrocytes was found to acquire significant free radical scavenging capability. However, this antioxidant property does not appear to be responsible for neuronal radioprotection. The ability of astrocytes to reduce radiation-induced neuronal toxicity appears to be mediated by a soluble protein(s) of mol. wt > 10 kDa.