Aim To investigate the serum microRNA-129-5p (miR-129-5p) level and its significance in patients with acute coronary syndrome (ACS). Methods 245 patients with ACS after percutaneous coronary intervention (PCI) admitted to our hospital from November 2016 to October 2017 were selected as subjects of study. According to the optimal cut-off point (0.92) of serum miR-129-5p in predicting the prognosis of ACS patients, the patients were divided into high miR-129-5p group (n＝109) and low miR-129-5p group (n＝136). The relative expression of miR-129-5p in serum was detected by real-time fluorescence quantitative PCR, and its relationship with the prognosis of ACS patients was analyzed. Results Major adverse cardiovascular events (MACE) occurred in 88 cases (35.92%) of 245 ACS patients after PCI. Area under curve of ROC, sensitivity, specificity and optimal cut-off point of serum miR-129-5p in predicting the prognosis of ACS patients were 0.3,9.55%, 77.71% and 0.92, respectively. The incidence of MACE in the high miR-129-5p group was higher than that in the low miR-129-5p group, the difference was statistically significant (P＜0.05). The median survival time of high miR-129-5p group was lower than that of low miR-129-5p group, the difference was statistically significant (P＜0.05). Cox regression analysis showed that chronic obstructive pulmonary disease, left ventricular ejection fraction, and miR-129-5p were closely associated with the prognosis of patients with ACS. Conclusion MiR-129-5p is closely related to the prognosis of ACS patients after PCI, and the detection of serum miR-129-5p level is helpful to understand the prognosis of patients.