BACKGROUND: Direct oral anticoagulants (DOACs) are commonly co-prescribed with amiodarone/diltiazem/verapamil, but whether there is a drug interaction between these drugs is unclear. OBJECTIVE: The purpose of this study was to investigate the risk of clinical outcomes associated with concomitant use of DOACs and amiodarone/diltiazem/verapamil. METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from January 1, 2011, to December 31, 2019. We used a cohort design to estimate hazard ratios for ischemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality, comparing DOACs + amiodarone/diltiazem/verapamil users and DOACs + beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window vs referent window within an individual also was conducted. RESULTS: Of 397,459 DOAC users, we included 9075 co-prescribed amiodarone, 9612 co-prescribed diltiazem, and 2907 co-prescribed verapamil. There was no difference in risk of any outcomes between DOACs + amiodarone/diltiazem/verapamil users vs DOACs + beta-blocker users in the cohort design. However, in the case-crossover design, we observed an odds ratio (OR) of 2.09 (99% confidence interval [CI] 1.37-3.18) for all-cause mortality associated with initiation of a DOAC while taking amiodarone, which was greater than that observed for DOAC monotherapy (OR 1.30; 99% CI 1.25-1.35). Similar findings were observed for cardiovascular mortality and all-cause mortality respectively with diltiazem. CONCLUSION: Our study showed no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem, or verapamil. Elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.