Low oxygen level or oxygen deficiency (hypoxia) is a major factor causing neuronal damage in many diseases. Inducing cell adaptation to hypoxia is an effective method for neuroprotection that can be achieved by either inhibiting the death effectors or enhancing the survival factors. Transcription coactivator p300 is necessary for hypoxia-induced transcriptional activation and plays an important role in neuron survival. However, the alteration of p300 expression under hypoxia condition and its role in hypoxia-induced neuronal damage remain unclear. In this study, the distribution of p300 in rat brain and the alteration of its expression in rat hippocampus during hypobaric hypoxia exposure were detected. In addition, the role of p300 in neuronal-like PC12 cell damage induced by oxygen deficiency (3% oxygen) was evaluated. Our results showed that p300 protein was mainly expressed in the cells expressed beta-tubulin III in the cerebral cortex, hippocampus, cerebellum cortex, medulla oblongata and hypothalamus. Less or no positive signal of p300 expression was observed in beta-tubulin III negative cells. This indicated that p300 was predominantly expressed in neurons of rat brain. Furthermore, p300 expression was up-regulated in rat hippocampus during hypoxia exposure and in neuronal-like PC12 cells under 3% oxygen condition. Interestingly, neuronal-like PC12 cell damage induced by oxygen deficiency (3% oxygen) was increased by suppression of p300 expression with short hairpin RNA (shRNA). These data indicate that p300 is an important molecule for neuroprotection under hypoxia.