We investigated the distribution and time course of expression of both gp130 mRNA and signal transducer and activator of transcription factor-3 (STAT3) in a rat model of ischemic tolerance induction. Forebrain ischemia was induced by four-vessel occlusion for 3 min as an ischemic preconditioning. Ischemic preconditioning 3 days before a 10-min lethal ischemia preserved neuronal signal. Expression of gp130 mRNA was induced 12 h after ischemic preconditioning, and was most prominent in the CA1 and the hilar region at 3 days, with expression sustained for at least 7 days. Ischemic preconditioning-induced STAT3 activation, as revealed by nuclear translocation, resembled that of gp130 expression. Nuclear STAT3 immunoreactivity occurred in the CA1 and the hilar region within 12 h after ischemic preconditioning, and was sustained for at least 7 days. Double-labeling experiments revealed that the cells expressing gp130 or STAT3 were glial fibrillary acidic protein (GFAP) immunoreactive astrocytes. These results demonstrate upregulation of gp130 and STAT3 in reactive astrocytes following ischemic preconditioning, indicating that this signal pathway is involved in the astroglial reaction to ischemic preconditioning in the rat hippocampus.