Myocardial ischemia and reperfusion (I/R)-induced tissue injury involve a robust inflammatory response. Our previous study found that TLR4-mediated MCP-1 production and monocytes accumulation contributes to the mechanism of myocardial injury following global myocardial I/R. Sialic acid binding Ig-like lectin receptors (Siglecs) have been implicated in the control of monocyte responses. We test the hypothesis that Siglec-E down-regulated TLR4-mediated inflammatory response following global myocardial I/R. Synergeneic heterotopic abdominal heart transplant was perfomed in mice strain (WT, TLR4-/-, Siglec-E-/-) for global myocardial I/R by using microsurgical techniques for vascular anastomoses. The donor's thoracic aorta was anastomosed end-to-side to the recipient's infrarenal abdominal aorta, and the donor's pulmonary artery was anastomosed to the recipient's inferior vena cava. Donor hearts were subjected to 4 h global ischemia followed by 4 h reperfusion. Our result shows that Siglec-E-/- donor heart significantly exaggerated monocyte/neutrophil recruitment myocardial injury and increased the inflammatory response (cytokines and chemochines). Interestingly the TLR4-activation signaling was significantly prevented by Siglec-E. We concluded that the use of Siglec-E might serve as a therapeutic clinical option in the treatment of cardiac injury induced by global myocardial I/R.