The dissociative anesthetic ketamine hydrochloride antagonizes the excitotoxic action of excitatory amino acids in the central nervous system. Proposals that the excitatory amino acid neurotransmitters may become excitotoxic and contribute to the pathophysiology of ischemic brain injury prompted us to examine ketamine in a model of global cerebral ischemia in gerbils. Pretreatment with anesthetic doses of ketamine ameliorated in a dose-dependent manner both behavioral and histopathological assessments of ischemic neuronal injury. These neuroprotective effects are proposed to result from a specific antiexcitotoxic rather than general anticonvulsant drug action. There may be clinical situations in which the neuroprotective actions of ketamine would be of therapeutic importance.