Objective To analyze the correlation of genetic polymorphism of miR-126 rs4636297 derived from platelet with anti-platelet reactivity of clopidogrel and clinical outcome in patients with acute coronary syndrome (ACS). Methods Consecutive ACS patients who were treated with clopidogrel and aspirin and underwent platelet reactivity test in 3d after stable antithrombotic therapy in Department of Cardiology, First Medical Center, Chinese PLA General Hospital from November 2015 to February 2017 were recruited in the study. Their peripheral blood samples were harvested to extract DNA to detect the polymorphism of miR-126 rs4636297. All patients were followed up for primary ischemic events within 1 year from discharging. SPSS statistics 22.0 was used for data analysis. Logistic regression analysis was used to study the independent influencing factors related to antiplatelet reactivity of clopidogrel and primary ischemic events within 1 year. Results A total of 364 patients were enrolled finally, and 193 of them were assigned into high on-treatment platelet reactivity (HTPR) group and the other 171 into the low on-treatment platelet reactivity (LTPR) group according to the results of platelet reactivity test. After adjustment, multivariate analysis indicated that the proportion of rs4636297 A allele was significantly larger in the HTPR group than the LTPR group (OR=1.85,95%CI:1.16-2.96; P=0.010). In the 1-year follow-up observation, the risk of primary ischemic events was obviously higher in the A allele carriers than the non-carriers (OR=4.09,95%CI:1.25-13.35; P=0.020). Conclusion The functional gene polymorphism rs4636297 of platelet-derived miR-126 may affect the response and outcome of clopidogrel antiplatelet therapy in ACS patients.