Epidermal growth factor (EGF), a conventional mitogenic factor, acts as a neurotrophic factor on several types of neurons in the central nervous system. We found that EGF prevented the death of rat cerebral cortical neurons cultured in a 50% oxygen atmosphere. This high-oxygen-triggered cell death showed features of apoptotic cell death, which was blocked by inhibitors of RNA or protein synthesis. EGF prevented the oxygen-induced death of the cultured cortical neurons in a dose-dependent manner. Basic fibroblast growth factor (bFGF) also prevented this cell death, although there was no apparent additive effect of EGF and bFGF. Among the cultured cortical neurons, we observed neurons possessing the EGF receptor and cells expressing c-Fos protein in response to EGF. The cortical neurons were cultured in the presence of cytosine arabinoside, and the number of glial fibrillary acidic protein-positive astroglial cells was >0.5% of that of the corresponding microtubule-associated protein 2-positive neurons. Therefore, the effect of EGF on the cultured cortical neurons is thought to be due to a direct action. We also examined EGF-induced signalling in the cultured cortical neurons. We found that EGF induced the sustained tyrosine phosphorylation of the EGF receptor and sustained the activation of mitogen-activated protein kinase in the cultured cortical neurons. We suggest that EGF may exert the survival effect through the prolonged activation of the EGF signalling.