WHAT'S KNOWN ON THIS SUBJECT:Neuronal apoptosis that follows hypoxia-ischemia is triggered by upregulation of NO synthase, with excessive accumulation of NO and release of excitatory amino acids such as glutamate. Animal studies demonstrated the ability of erythropoietin to attenuate these mechanisms. WHAT THIS STUDY ADDS:The administration of erythropoietin to infants with asphyxia with mild/moderate HIE was associated with favorable decreases in endogenous NO production, decreases in seizure activity, and improved neurodevelopmental outcomes to 6 months of age. abstract OBJECTIVE: The goal was to examine biochemical, neurophysiologic, anatomic, and clinical changes associated with erythropoietin administration to neonates with hypoxic-ischemic encephalopathy (HIE). METHODS:We conducted a prospective case-control study with 45 neonates in 3 groups, a normal healthy group (N ϭ 15), a HIEerythropoietin group (N ϭ 15; infants with mild/moderate HIE who received human recombinant erythropoietin, 2500 IU/kg, subcutaneously, daily for 5 days), and a HIE-control group (N ϭ 15; did not receive erythropoietin). Serum concentrations of nitric oxide (NO) were measured at enrollment for the normal healthy neonates and at enrollment and after 2 weeks for the 2 HIE groups. The 2 HIE groups underwent electroencephalography at enrollment and at 2 to 3 weeks. Brain MRI was performed at 3 weeks. Neurologic evaluations and Denver Developmental Screening Test II assessments were performed at 6 months. RESULTS:Compared with normal healthy neonates, the 2 HIE groups had greater blood NO concentrations (P Ͻ .001). At enrollment, the 2 HIE groups did not differ in clinical severity, seizure incidence, NO concentrations, or electroencephalographic findings. At 2 weeks of age, electroencephalographic backgrounds improved significantly (P ϭ .01) and NO concentrations decreased (P Ͻ .001) in the HIEerythropoietin group, compared with the HIE-control group; MRI findings did not differ between groups. At 6 months of age, infants in the HIE-erythropoietin group had fewer neurologic (P ϭ .03) and developmental (P ϭ .03) abnormalities. CONCLUSION:This study demonstrates the feasibility of early administration of human recombinant erythropoietin to term neonates with HIE, to protect against encephalopathy.