Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5% O2 for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67% ± 7% of neocortex in unmedicated rats to 32% ± 8%, 51% ± 12%, 38% ± 19%, and 53% ± 10% when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells was reduced from 156 ± 33 neurons to 12 ± 7 (0 hour, p < 0.01) and 37 ± 17 (1 hour, p < 0.05). These effects were obtained at plasma concentrations (60 to 120 mg/ml) that have occasionally been reached without serious toxicity in human anticonvulsant trials. These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours.