Objectives: This study examines the efficacy of puerarin, a drug used in traditional Chinese medicine, in attenuating ischemic brain injury after cerebral ischemia and reperfusion, and explores possible mechanisms underlying neuroprotective effects. Methods: The animal model of ischemia/reperfusion injury was induced by middle cerebral artery occlusion for 2 hours followed by up to 72 hour reperfusion. The rats were randomly assigned into four groups (n = 6/group): puerarin at 100, 200 and 400 mg/kg or saline, administered intraperitoneally. Neurological outcome and infarct volume by 2% triphenyl tetrazolium chloride staining were determined 72 hours after reperfusion. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining was used to detect the cell damage of brains (n = 5/group). Erythropoietin activation was detected by enzyme-linked immunosorbent assay (n = 5/group). Results: Compared with the vehicle saline group, puerarin decreased infarction volume at doses of 200 mg/kg (p = 0.045) and 400 mg/kg (p = 0.0002), but not at 100 mg/kg (p = 0.387). Functional neurological outcome was improved with puerarin at 400 mg/kg (p = 0.015), but not at 100 mg/kg (p = 0.68) or 200 mg/kg (p = 0.056). Puerarin significantly decreased the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling staining cells compared with the vehicle group 4, 24 and 72 hours after reperfusion. The erythropoietin activity was higher in puerarin treated group compared with the vehicle group. Discussion: Puerarin has neuroprotection effects in rats at doses of 200 and 400 mg/kg, administered intraperitoneally after transient middle cerebral artery occlusion which may be partly due to activation of erythropoietin activity. [Neurol Res 2009; 31: 402-406]