Background Monocyte chemoattractant protein-1 (MCP-1) and its major receptor, CC chemokine receptor 2 (CCR2), have been shown to contribute to left ventricular remodeling after myocardial infarction. However, it is unknown whether CCR2 deficiency protects the myocardium after myocardial ischemia-reperfusion. The purpose of the present study was to investigate the effects of CCR2 deficiency on myocardial ischemia-reperfusion injury in mice. Methods and Results Experiments were performed in CCR2-/-and wild-type mice subjected to 45 min of ischemia followed by reperfusion. Macrophage infiltration in ischemic lesions was markedly reduced in CCR2-/-mice compared with wild-type mice (p< 0.01). The infarct size was significantly reduced in CCR2-/-mice compared with wild-type mice at 3 days after reperfusion (p< 0.001). In situ zymography revealed augmented gelatinolytic activity at 3 days after reperfusion in wild-type mice, but significantly less activity in CCR2-/-mice. NADPH oxidase activity, the intensity of nitrotyrosine staining and expression of inducible nitric oxide synthase and thioredoxin-1 were significantly increased in ischemic myocardium in wild-type mice compared with CCR2-/-mice, indicating a role for CCR2 in oxidative stress after ischemia-reperfusion. Conclusions Inhibition of the MCP-1/CCR2 pathway may be a useful strategy for attenuating myocardial ischemia-reperfusion injury.(Circ J 2006; 70: 342-351)