Perinatal hypoxic-ischemic brain injury remains a significant clinical problem for which there remains no adequate therapeutic intervention. Apolipoprotein E (apoE) is a 299 amino acid protein that has been demonstrated to modify functional recovery following acute ischemic and traumatic brain injury. The aim of the current study was to evaluate whether administration of an apoE-derived peptide could reduce CNS injury in a rodent model of perinatal hypoxia and ischemia. We found that intrathecal delivery of an apoE-mimetic peptide caused a significant reduction in post-ischemic brain necrosis, as reflected by decreased reduction in ipsilateral brain weight 7 days following hypoxic-ischemic injury. These results suggest that administration of an apoE-derived therapeutic peptide represents a novel therapeutic strategy in the clinical setting of perinatal hypoxic-ischemic injury.