Abstract: AIM:To investigate the role of CXCR3 in cardiac ischemia-reperfusion injury (IRI). METHODS: IRI rat model was set up and fresh myocardium tissues were obtained from sham and 2, 6, 9, and 12 h models after IRI. Expressions of CXCL9-11 and their receptor, CXCR3, were detected by real-time and Western blot. The effect of CXCR3 was blocked by its specific antagonist 6C. Myocardial injury was estimated by activity of cardiac-related enzyme activity and morphological indices. The distribution of subset of infiltrated T cells was analyzed by flow cytometry. RESULTS: Significant upregulation of both CXCL9-11 and CXCR3 was detected in varied time frames after reperfusion. Blockage of CXCR3 exerted structural and functional protective effects that were verified and were due to immunomodulation of myocardial tissues by CXCR3 of downregulation of Th1 and upregulation of T-regs. CONCLUSION: CXCR3 is an ideal therapeutic target in cardiac IRI due to its immunomodulatory effect.