We assessed the cerebral protective effects of the competitive interleukin-1 antagonist rhIL-1ra in 7-day-old rats that were subjected to brain hypoxia-ischemia by unilateral carotid artery ligation and subsequent exposure to 2 h of 7.5% O2-balanced N2. This procedure leads to atrophy in the cerebral hemisphere ipsilateral to carotid occlusion, with prominent foci of neuronal infarction in the striatum. Systemic administration of 100 mg/kg of rhIL-1ra before and/or after the hypoxic exposure limited the insult. The results indicate that rhIL-1ra has potent neuroprotective properties against morphologic brain injury from hypoxia-ischemia. rhIL-1ra may prove to be clinically useful in protecting against hypoxia-ischemia-related disorders.