To separately analyze the hypoxic component of hypoxic-ischemic encephalopathy, rats were prepared such that their paO2 was maintained at 20 mmHg while maintaining systemic arterial pressures. During the 20-min experiment, brain oxygen concentration and extracellular amino acid concentrations were monitored. At sacrifice, the brains were studied for morphologic evidence of injury by immunocytochemical staining for the non-constitutive stress protein HSP-72 or neuronal death by acid fuchsin staining. Oxygenated rats subjected to global ischemia were prepared for comparison. In these experiment, hypoxia resulted in no increase in extracellular glutamate concentration, and no morphologic injury was detected. Thus, hypoxia without ischemia is well tolerated by brain.