Abstract Background The association between ABO blood groups and the risk of thrombosis and bleeding in patients with coronary artery disease has been of interest for many years, but the mechanisms are not fully understood. Aim To investigate the relationship between the ABO blood groups and the platelet reactivity in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Methods We examined 10,724 consecutive PCI patients in China from January 2013 to December 2013.Among them, 6,740 patients had the results of thromborlastogram (TEG) and the ABO blood groups. Low on-treatment platelet reactivity (LTPR) was defined as adenosine diphosphate-induced platelet maximum amplitude of TEG<31mm. Results A total of 6,740 PCI patients (mean age, 58.23±10.27; male, 77.6%) treated with clopidogrel were finally enrolled for analysis. There were 2560 (37.98%) patients in LTPR group. In this group, the multivariate logistic regression showed that the blood group A (OR: 0.885, 95%CI 0.789-0.993, p=0.038) was independent protective factor in the A/non-A model (model 1). Then, we further divided the non-A groups into B, O, AB groups to set the model 2. In model 2, compared to A, multivariate logistic regression showed that only the blood group B (OR: 1.157, 95%CI 1.015-1.320, p=0.030) was independent risk predictors for LTPR, representing a higher risk of bleeding. Conclusions In the large sample real-world study, we reported the relationship between ABO blood groups and platelet reactivityin PCI patients treated with clopidogrel for the first time. Blood group A was an independent protective factor for LTPR, representing a lower risk of bleeding, whereas blood group B was an independent risk factor for LTPR, representing a higher risk of bleeding. These results provide an interesting perspective on blood groups and individualized antithrombotic therapy in patients with coronary artery disease, and further elucidation of the mechanisms is still needed in the future.