AbstractBackgroundMonocytes and fibrinogen (FIB) play important roles in driving acute and reparative inflammatory pathways after myocardial infarction (MI). In humans, there are three subsets of monocytes, namely, CD14++CD16− (Mon1), CD14++CD16+ (Mon2), and CD14+CD16++ (Mon3). During the inflammatory response, monocyte subsets express high levels of integrin αMβ2and protease‐activated receptors 1 and 3 to interact with FIB.HypothesisHowever, whether there is a synergistic role of FIB combined with Mon2 counts in prioritizing patients at high risk of future major adverse cardiovascular events (MACEs) after MI remains unknown.MethodsThe MI patients who treated with primary percutaneous coronary intervention were enrolled. MI patients were categorized into four groups, that is, low FIB/low Mon2, low FIB/high Mon2, high FIB/low Mon2, and high FIB/high Mon2, according to cutoff values of 3.28 g/L for FIB and 32.20 cells/μL for Mon2. Kaplan−Meier survival analysis and Cox proportional hazards models were used to estimate the risk of MACEs of MI patients during a median follow‐up of 2.7 years. Mediating effects of high FIB levels and MACEs associated with high monocyte subsets were calculated by mediation analysis.ResultsHigh FIB/high Mon2 group had the highest risk of MACEs during a median follow‐up of 2.7 years. Moreover, mediation analysis showed that a high FIB level could explain 24.9% (p< .05) of the increased risk of MACEs associated with Mon2.ConclusionThis work provides evidence indicating the translational potential of a synergistic role of FIB combined with Mon2 in prioritizing patients at high risk of future MACEs after MI.