Neonatal unconjugated hyperbilirubinemia might cause severe bilirubin neurotoxicity in especially hemolytic conditions. The study aimed to elucidate the potential neuroprotective effects of erythropoietin (EPO) in hemolysis-induced hyperbilirubinemia. In newborn rats, hyperbilirubinemia secondary to hemolysis was induced by injecting with phenylhydrazine hydrochloride (PHZ) and rats were injected with either vehicle or EPO. At 54th hour of the PHZ injection, rats were decapitated. Serum levels of TNF-alpha, IL-1 beta, IL-10, brain-derived neurotrophic factor (BDNF) and S100-B and brain malondialdehyde, glutathione levels and myeloperoxidase activities were measured. TUNEL staining and NF-kappa B expression were evaluated. As compared to control pups, in vehicle-treated PHZ group, TNF-alpha and IL- 1 beta levels, malondialdehyde level and myeloperoxidase activity were increased with concomitant decreases in IL-10 and glutathione. All EPO regimens reversed PHZ-induced alterations in IL-10, TNFa, malondialdehyde and glutathione levels. Three-daytreatment abolished increases in myeloperoxidase activity and IL-1 beta levels, while BDNF and S100-B were elevated. Increased TUNEL (+) cells and NF-kappa B expressions in the brain of PHZ group were reduced in the 3-day-treated group. EPO exerted anti- inflammatory effects on PHZinduced neural damage in newborn rats, while the neuroprotection was more obvious when the treatments were repeated successively. The results suggest that EPO treatment may have a therapeutic potential in supporting neuroplasticity in the hyperbilirubinemic neonates.