OBJECTIVE: Our purpose was to determine whether hypoxic-ischemic brain damage would be protected against by advance conditioning of the animal with 4 hours of hypoxic exposure. STUDY DESIGN: Neonatal rats were exposed on postnatal day 7 to (1) 4 hours of hypoxia with 8% oxygen (preconditioning hypoxic group) or (2) 4 hours of normoxia (sham-preconditioning group). At 24 hours after the conditioning, rats from both groups were exposed to left carotid artery ligation followed by 2 hours of hypoxia (8% oxygen/92% nitrogen). All the rats were killed 1 week after hypoxia-ischemia, and their brains were extracted for histologic study. RESULTS: Two types of brain damage were histologically observed at 1 week after hypoxia-ischemia in both groups (1)generalized infarction in the ligated hemisphere and (2) predominant neuronal loss in the hippocampal region. The total incidence of brain damage was significantly decreased in the preconditioning hypoxic group (10/24 rats, 41.7%) compared with the sham-preconditioning hypoxic group (17/22 rats, 77.3%; P < .05). CONCLUSION: Our results show that the hypoxic- ischemic tolerance phenomenon may be induced in the hypoxic-ischemic brain damage model by conditioning the animal before the insult with 4 hours of hypoxic exposure.