To investigate whether nitric oxide (NO) plays a role in the neurotoxicity produced by N-methyl-D-aspartate (NMDA) we have examined the effects of NO inhibitors on NMDA-mediated neurodegeneration in the CA1 region of rat hippocampal slices. L-NG-Monomethylarginine, L-NG-nitroarginine and hemoglobin markedly diminished the toxicity produced by activation of NMDA receptors without interfering with NMDA receptor-mediated ion currents or synaptic responses. The neuroprotective effects are reversed by coapplication of L-arginine with the NO synthase inhibitors. These results suggest that activation of the NO system is an important component of the biochemical cascade leading to neurodegeneration produced by NMDA receptors.