Hypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. To date, few therapeutic strategies could provide complete neuroprotection. Erythropoietin (EPO) has been shown to be beneficial in several models of neonatal HI. This study examines the effect of treatment with erythropoietin on postnatal day 2 (P2) rats introduced with HI injury.Rats at P2 were randomized into four groups: sham, bilateral carotid artery occlusion (BCAO), BCAO + early EPO, and BCAO + late EPO groups. Pups in each group were injected with either saline or EPO (5000U/kg) intraperitoneally once at immediately (early) or 48h (late) after HI induction. Body weight was assessed at P2 before and day 7 after HI. Mortality Rate was assessed at 24h, 48h and 72h after HI and brain water content was assessed at 72h. Brain weight and expression of myelin basic protein (MBP) were assessed at day 7 and day 14. At day 31 to 35 following HI insult, neurological behavior function was assessed via Morris water maze (MWM) test.HI cause significant higher mortality in male than in female (P=0.0445). Among the surviving animal, HI affect significantly the body growth, brain growth, MBP expression, and neurological behavior. EPO treatments at both early and late time points significantly benefit the rats in injury recovery, in which they promoted weight gains, reduced brain edema, as well as improved spatial learning ability and memory.We demonstrated a single dose of EPO at 5000U/kg immediately or 48h after HI injury had significant benefit for the P2 rats in injury recovery, and there was no adverse effect associated with either EPO treatment.