Objectives: The neuroprotective effect of erythropoietin has been demonstrated by ischemia and reperfusion models in adult and neonatal rodents. However, administration of high-dose erythropoietin has potential complications. The goal of this study was to determine whether local infusion of low dose erythropoietin offers neuroprotective effects after ischemia and reperfusion injury. Methods: Adult male Sprague-Dawley rats subject to middle cerebral artery occlusion were randomly divided into three groups: (1) sham group: the rats received the same procedure as the other two groups except that no suture was inserted; (2) vehicle group: intra-artery local infusion of saline was administered via middle cerebral artery after reperfusion; and (3) treatment group: 50 U/kg intra-artery local infusion of erythropoietin was administered via middle cerebral artery after reperfusion. Neurological deficit scores and infarct volume (determined by hematoxylin-eosin staining) were evaluated 48 hours after reperfusion. Apoptosis was measured through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expression of vascular endothelial growth factor and phosphorylated extracellular signal-regulated kinase were investigated by immunohistochemistry method. Results: The results show that intra-artery local infusion of erythropoietin, via the middle cerebral artery, significantly reduced neurological deficit scores, foot fault number, and the infarct volume at 48 hours after reperfusion. Significant reductions were also found in the number of positive cells stained by TUNEL assay within the ischemic core and penumbra. Furthermore, local infusion of erythropoietin increased the expression of phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor. Discussion: Local infusion of low-dose erythropoietin via the middle cerebral artery is shown to be neuroprotective against cerebral ischemia and reperfusion injury. The mechanism of neuroprotection may be associated with the increased expression of phosphorylated extracellular signal-regulated kinase and vascular endothelial growth factor.