OBJECTIVES: To investigate the risk of thrombosis and bleeding according to multiple antithrombotic treatment regimens in atrial fibrillation (AF) patients after myocardial infarction (MI) or percutaneous coronary intervention (PCI) BACKGROUND: The optimal antithrombotic treatment strategy is unresolved in patients with multiple indications. METHODS: A total of 12,165 AF patients hospitalized with MI and/or undergoing PCI between 2001-2009 were identified by nationwide registries (60.7% males, mean age 75.6 years). Risk of MI/coronary death, ischemic stroke, and bleeding according to antithrombotic treatment regimen was estimated by Cox regression models. RESULTS: Within one year, MI or coronary death, ischemic stroke, and bleeding events occurred in 2,255 (18.5%), 680 (5.6%), and 769 (6.3%) patients, respectively. Relative to triple therapy (oral anticoagulation (OAC) + aspirin + clopidogrel), no increased risk of recurrent coronary events was seen for OAC + clopidogrel (hazard ratio [HR] 0.69 [0.48-1.00]), OAC + aspirin (HR 0.96 [0.77-1.19]), or aspirin + clopidogrel (HR 1.17 [0.96-1.42]), but aspirin + clopidogrel resulted in a higher risk of ischemic stroke (HR 1.50 [1.03-2.20]). Also, OAC + aspirin and aspirin + clopidogrel were associated with a significant increased risk of all-cause death (HR 1.52 [1.17-1.99] and 1.60 [1.25-2.05]). When compared to triple therapy, bleeding risk was non-significantly reduced for OAC + clopidogrel (HR 0.78 [0.55-1.12]) and significantly reduced for OAC + aspirin and aspirin + clopidogrel. CONCLUSION: In real-life AF patients with indication for multiple antithrombotic drugs after MI/PCI, OAC and clopidogrel was equal or better on both benefit and safety outcomes compared to triple therapy.