BACKGROUND Dual antiplatelet therapy is the main treatment for cardiovascular diseases (CADs). In this study, we evaluated the efficacy and safety of aspirin combined with low-dose rivaroxaban in the secondary prevention of high-risk ischemic cardiovascular diseases. MATERIAL AND METHODS In total, 168 patients who were diagnosed with acute myocardial infarction or multiple vessel disease 1 year after percutaneous coronary intervention were divided into 2 groups: the aspirin group (aspirin as acetylsalicylic acid: 100 mg once daily) and the aspirin + rivaroxaban group (aspirin: 100 mg once daily, rivaroxaban: 2.5 mg twice daily). The patients were followed up for 2 years to assess the clinical efficacy and safety of a new dual-channel antithrombotic treatment strategy. RESULTS The occurrence of MACE (recurrent myocardial infarction, in-stent restenosis, coronary target vessel revascularization, stent thrombosis, heart failure, rehospitalization, and all-cause mortality) in the rivaroxaban + aspirin group was lower than that in the aspirin group (3.57% of patients received aspirin + rivaroxaban treatment vs 13.10% of patients received aspirin treatment). There were not more adverse events in the rivaroxaban + aspirin group than in the aspirin group. Compared with patients administered aspirin, the coagulation function of patients taking aspirin + rivaroxaban was significantly changed. No heart failure occurred in either group of patients with CADs. CONCLUSIONS Aspirin + rivaroxaban had better primary outcome and secondary outcomes in patients with a high risk of ischemia. Our results provide a basis for evaluating the efficacy and safety of drugs used in secondary prevention among patients with high risk of ischemia.