The neuroprotective effect of docosahexaenoic acid (DHA) on the glutamate-induced cytotoxicity in rat hippocampal cultures was investigated in the present study. DHA at 5-50 microg/ml successfully protected neurons against the cytotoxicity, markedly increased the cell viability, inhibited both nitric oxide (NO) production and calcium influx, and increased the activities of antioxidant enzymes of glutathione peroxidase (GSH-Px) and glutathione reductase (GR). However, it did not alter the levels of glutathione (GSH) as compared to the control. These results suggest that DHA might be a potent neuroprotector. In addition, they may help to improve our understanding of the effect of DHA on neurodegeneration.