Early diagnosis is critical for the appropriate management of patients with acute coronary artery syndrome (ACS). An ability to predict eventual myocardial infarct size (IS) would be advantageous in the efficient provision of healthcare delivery service. Currently, serial measurement of cardiac standard biomarkers e.g. high-sensitive troponin I/T (hsTnI/T) or creatine kinase (CK-MB) are not informative at the earliest time of patients contact and are unable to predict the final extent of myocardial damage. Therefore, identifying novel biomarkers for early diagnosis, risk stratification and therapeutic potential are clearly warranted. Macrophage migration inhibitory factor (MIF) has a broad distribution and is expressed by monocytes, macrophages, T-cells, vascular smooth muscle cells and cardiomyocytes. In the heart MIF can be rapidly released from cardiac cells upon ischemic insult, therefore there is a potential to be a novel biomarker in diagnosis and prediction of ACS. In this report, we explored the changes in both animal model and clinical patients with ACS. Elevation of MIF plasma level could be detected at admission and the MIF level at the earliest time point had very good positive correlations with IS, cardiac remodeling and functional decline detected by magnetic resonance imaging (MRI). This predictive capacity was observed not only at acute phase but also at chronic phase after acute MI. Moreover, a sustained elevation of plasma MIF level was noticed in both animal model and clinical patients, which was associated with inflammatory cell infiltration and cell work revealed that peripheral blood monocytes (PBMC) was the major contributor responsible to the heightened MIF levels sustained at day-3 post-MI. Further, increased MIF levels at admission could predict in-hospital mortality similar as hs-TnI/T, but only the MIF level was able to predict long-term major adverse cardiovascular events. These results indicate an excellent potential of MIF as a novel biomarker in diagnosis and risk identification of acute MI.