Although isoflurane can reduce ischemic neuronal injury after short postischemic recovery intervals, data from our laboratory have demonstrated that this neuroprotection is not sustained and that delayed apoptotic neuronal death, mediated in part by activation of caspases, contributes to the gradual increase in the size of the infarction. We tested the hypothesis that the neuroprotective efficacy of isoflurane can be prolonged with the administration of z-IETD-fmk, a specific inhibitor of caspase 8. Fasted Wister rats were anesthetized with isoflurane and randomly allocated to awake-vehicle, isoflurane-vehicle, awake-IETD, or isoflurane-IETD groups (n = 25 per group). Animals were subjected to 60 min focal ischemia by filament occlusion of the middle cerebral artery (MCAO). Daily intracerebroventricular injections of z-IETD-fmk or vehicle were administered via an implanted cannula starting before ischemia and continuing until 14 days post-MCAO. Neurological assessment was performed 14 days after ischemia after which the volume of cerebral infarction and number of intact neurons in the peri-infarct cortex were determined. Total infarction volume was less in the isoflurane-IETD group than in awake-vehicle, isoflurane-vehicle, and awake-IETD groups. Infarction volume was also less in the awake-IETD group versus the awake-vehicle group. The number of intact neurons within the peri-infarct cortex was significantly less in the awake-vehicle group in comparison with the other three experimental groups. The isoflurane-IETD group had better neurologic outcomes than both vehicle-treated groups at 14 days post-MCAO. These results suggest that a combination of isoflurane and a caspase 8 inhibitor can produce neuroprotection that is evident even after a recovery period of 14 days. This combination demonstrated greater efficacy than the administration of either isoflurane or z-IETD-fmk alone. These results are consistent with the premise that continuing apoptosis contributes to the enlargement of cerebral infarction during the recovery period and that its inhibition can provide sustained neuroprotection.