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Abstract Background Membrane-associated fibrinogen-like protein 2 (FGL2 prothrombinase, p FGL2) is abundantly expressed in activated microvascular endothelial cells (MVECs) and plays a crucial role in microthrombus formation in microcirculatory vasculature. It has been widely reported that coronary microvascular obstruction (CMVO) contributes to adverse outcomes following myocardial ischemia/reperfusion. However, the role of p FGL2 in CMVO is poorly understood. Methods and results We aimed to identify the effect of MVECs- p FGL2 in CMVO using FGL2 knockout mice. As results, the MVECs- p FGL2 expression progresses significantly over 3 days and then gradually decreases, which is positively correlated with the extent of CMVO as detected by HE staining in wild type mice. Furthermore, FGL2 deficiency is correlated with decreased areas of no-reflow and necrosis as detected by Evans Blue and TTC staining and that it ameliorates cardiac dysfunction detected by hemodynamics in the early stage of CMVO. Moreover, fibrin deposition in microvasculature is significantly reduced in FGL2-deficient mice as evidenced by immunohistochemistry, MSB and Carstairs staining, along with the down-regulation of leukocyte adhesion and infiltration. Additionally, we observed that the FGL2 deficiency decreases macrophage infiltration and shifts the macrophage phenotype from pro-inflammatory (M1,) to anti-inflammatory (M2,) pattern in the early stage of CMVO. Conclusion These findings highlight the MVECs- p FGL2-fibrin pathway in the early stage of CMVO and provide insights into coagulation and inflammation for the coronary artery disease therapeutics. Highlights • Decreased expression of p FGL2 contributes to CMVO amelioration. • p FGL2-fibrin pathway is responsible for CMVO by regulating leukocyte stasis and macrophage polarization. • p FGL2 deficiency may represent a novel therapeutic approach to protect against CMVO following myocardial I/R. [ABSTRACT FROM AUTHOR]