X-linked inhibitor of apoptosis protein (XIAP) is a potent suppressor of neuronal death. The aim of this study was to investigate the expression of XIAP after ischemia in the human and rat developing brain. Autopsy specimens from 19 children with neuropathologic diagnosis of focal cerebral ischemic infarct were processed immunohistochemically for XIAP expression. XIAP positive cells were compared in pathologically classified acute (1-4 d), subacute (5-30 d), and chronic (months) strokes vs. age-matched controls with normal brain histology. For the animal studies, ischemia was induced in 1-wk-old rats by unilateral carotid artery occlusion and transient hypoxia. XIAP expression was quantified at four time points after ischemia in the infarct core and peri-infarct area. Neuronal XIAP expression was higher in the penumbra of subacute human infarcts compared with controls (p Ͻ 0.05). XIAP expression in the peri-infarct of rat pup was highest at 7 d postischemic injury (p Ͻ 0.05). The increase in XIAP expression was associated with a reduction in activated caspase-3 in ischemic neonatal rat brain. Our results demonstrate that XIAP expression postischemic injury is delayed in both species and may continue for several days. Therefore, potentiation of XIAP expression may be neuroprotective in the developing brain. (Pediatr Res 65: 21-26, 2009)