Erythropoietin (EPO) and its receptor (EPO-R) play a central role in erythropoiesis and neuroprotection. This study investigates the neuroprotective effects of systemic administration of recombinant human EPO (r-Hu-EPO) in various animal models of brain injury. The authors found that EPO-R is expressed at brain capillaries, suggesting a route for EPO to enter the brain. Systemic administration of r-Hu-EPO before or up to 6 hours after focal brain ischemia significantly reduced injury by 50-75%. Additionally, r-Hu-EPO ameliorated concussive brain injury, experimental autoimmune encephalomyelitis, and kainate-induced seizures. The safety profile of r-Hu-EPO supports clinical trials as a potential neuroprotective treatment. The mechanism of action may involve activation of antiapoptotic genes and modulation of inflammation and neuronal excitability.Erythropoietin (EPO) and its receptor (EPO-R) play a central role in erythropoiesis and neuroprotection. This study investigates the neuroprotective effects of systemic administration of recombinant human EPO (r-Hu-EPO) in various animal models of brain injury. The authors found that EPO-R is expressed at brain capillaries, suggesting a route for EPO to enter the brain. Systemic administration of r-Hu-EPO before or up to 6 hours after focal brain ischemia significantly reduced injury by 50-75%. Additionally, r-Hu-EPO ameliorated concussive brain injury, experimental autoimmune encephalomyelitis, and kainate-induced seizures. The safety profile of r-Hu-EPO supports clinical trials as a potential neuroprotective treatment. The mechanism of action may involve activation of antiapoptotic genes and modulation of inflammation and neuronal excitability.