Recent evidence in primary neuronal cell culture implicates nitric oxide (NO) as a mediator of glutamatergic neurotoxicity acting via N-methyl-D-aspartate (NMDA) receptors. We find that administration of the potent nitric oxide synthetase (NOS) inhibitor NG-nitro-L-arginine (NO-Arg) at 50 mg/kg to 100 mg/kg i.p. to 6-day old Sprague-Dawley rat pups results in prompt and long-lasting in vivo inhibition of NOS. Fifteen hours after administration, NO-Arg produces essentially complete neuroprotection against hypoxic-ischemic in a standard (Rice-Vanucci) model. These results support the hypothesis that NO may play a key mediatory role in brain damage attending focal ischemic stroke.