The therapeutic application of barbiturate-induced coma was evaluated in a primate model of focal cerebral ischemia. A standardized regimen of pentobarbital was used, and the times of initiation of administration were varied following a 6-hour middle cerebral artery occlusion in baboons. Three groups of five animals were treated at 30, 120, and 240 minutes after occlusion, while one group of five animals received no barbiturate therapy. Complete protection from intracranial pressure (ICP) elevation and ischemic damage was seen only in the group treated at 30 minutes. Those treated at 120 minutes, while doing better than untreated animals, still had ICP elevation and a marked neuropathological deficit. Animals treated at 240 minutes suffered a detrimental effect, in that malignant ICP and marked ischemic damage occurred earlier than in the untreated animals. The safe "therapeutic window" for barbiturate-induced coma in this animal model does not extend beyond 2 hours. Delayed administration results in a deleterious response and not merely a lack of protection.