The effect of γ-hydroxybutyrate on the histological and behavioral consequences of transient brain ischemia was studied in the four vessel occlusion rat model. In saline-treated animals, 30 min ischemia caused a massive loss of neurons in the hippocampal CA1 subfield (normal neurons: 14%, 5%, 23% and 30% on the 3rd, 10th, 15th and 65th day after ischemia, respectively). γ-Hydroxybutyrate — 300 mg/kg intraperitoneally (i.p.) 30 min before or 10 min after arteries occlusion, followed by 100 mg/kg i.p. twice daily for the following 10 days — afforded a highly significant protection (normal neurons on the 3rd, 10th, 15th and 65th day after ischemia: 88% and 91%, 80% and 80%, 91% and 90%, 72% and 71% in rats receiving the first dose before or after arteries occlusion, respectively). The ischemia-induced sensory–motor impairment was significantly attenuated in rats receiving the first dose of γ-hydroxybutyrate before arteries occlusion. Finally, the ischemia-induced impairment in spatial learning and memory, evaluated starting 27 days after the ischemic episode, was significantly attenuated by γ-hydroxybutyrate, either injected first at 30 min before or 10 min after arteries occlusion. Lower doses of γ-hydroxybutyrate had no significant effect. In conclusion, these results indicate that γ-hydroxybutyrate provides significant protection against both histological and behavioral consequences of transient global cerebral ischemia in rats.