Background: We have previously shown that erythropoietin (Epo) exerts neuroprotective effects in the Rice-Vannucci model of neonatal hypoxic-ischemic brain injury. However, the mechanisms of Epo protection in this model are still unclear. Objectives: In the present study, we studied the effects of systemically administered Epo on lipid peroxidation levels and antioxidant enzyme ( superoxide dismutase and glutathione peroxidase) activities following hypoxic-ischemic brain injury in neonatal rats. Methods: Seven-day-old Wistar rat pups were subjected to left carotid artery occlusion followed by 2.5 h of hypoxic exposure. Brain lipid peroxidation levels and antioxidant enzyme activities were measured in the injured hemispheres 24 h after the hypoxic-ischemic insult. Results: Hypoxic-ischemic injury significantly increased the thiobarbituric acid-reactive substance levels in the injured hemispheres as compared to the control group. In addition, glutathione peroxidase activity was significantly elevated in Epo-treated animals compared to saline-treated animals and the control group. Conclusions: These results suggest that Epo exerts neuroprotective effects against hypoxic-ischemic brain injury at least partially via the modulation of antioxidant enzyme activity. Copyright (C) 2005 S. Karger AG, Basel.