The signal transducers and activators of transcription (STAT) proteins are a group of transcriptional factors. Among them, STAT5 initiates a pro-survival signaling cascade. So far, little has been known about the role of STAT5 in cerebral ischemia and reperfusion. This study examines the phosphorylation status of STAT5 in hippocampal CA1 in the early stage after transient global cerebral ischemia in rats. Our data show that the phosphorylation of STAT5 was increased in hippocampal CA1 at 1h and 3h ischemia. Taking advantage of the neuroprotective effect of erythropoietin (EPO) in CA1, we further demonstrated that the administration of EPO enhanced the phosphorylation of STAT5, with SATA5a being phosphorylated earlier. The enhanced phosphorylation of STAT5 in the EPO-treated group was accompanied by the upregulation of STAT5 downstream gene products, Bcl-xL and XIAP. Consequently, ischemic CA1 neuronal damage was attenuated by the administration of EPO. Both the enhancement of STAT5 phosphorylation and the neuroprotection rendered by EPO were blocked by Tyrphostin, a selective inhibitor for Janus kinase 2, which is an upstream kinase of STAT5. These findings suggest an association between the activation of STAT5 and CA1 neuronal survival after cerebral ischemia.