This study aimed to compare and determine the prevalence of drug–drug interaction (DDI) and bleeding rate in atrial fibrillation (AF) patients receiving anticoagulants in a clinical setting. We used large claims data of AF patients obtained from the Japan Medical Data Center. The prevalence of DDIs and cases leading to bleeding events were surveyed clinically relevant DDIs extracted from 1) reported from a spontaneous adverse event reporting system (Japanese Adverse Drug Events Report system; JADER) ≥4 patients; 2) DDIs cited in the package inserts of each anticoagulant (each combination assessed according to “Drug interaction 2015” list; 3) warfarin and quinolone antibiotics DDIs. DDIs were categorized the mechanisms for pharmacokinetic DDI (Cytochrome P450 (CYP) or transporter etc. that modulate blood concentration of anticoagulants)/pharmacodynamic DDI (combination with similar pharmacological actions) or both in the analysis for each patients’ prescriptions obtained from a claims data. AF patients were compared between cases with and without bleeding after administered of anticoagulants. Bleeding was observed in 220/3290 (6.7%) AF patients. The bleeding rate in patients with both pharmacokinetic and pharmacodynamic DDI mechanisms (26.3%) was higher than that in patients with either mechanism (8.6% and 9.2%, respectively) or without DDIs (4.9%). The odds ratio for bleeding in AF patients with both of pharmacokinetic and pharmacodynamic was (7.18 [4.69–11.00], p<0.001). Our study concluded multi mechanism based DDIs leads serious outcome as compared to that of single mechanism based DDIs in AF patients. We determined the prevalence and frequency of bleeding for anticoagulant-related DDIs. To manage DDIs, both pharmacokinetic and pharmacodynamic DDI mechanisms should be closely monitored for initial symptoms of bleeding within the first 3 months.