BACKGROUND: Although drug interactions between clarithromycin/erythromycin/fluconazole and direct oral anticoagulants (DOACs) are mechanistically plausible, it is uncertain whether they are clinically relevant. OBJECTIVE: This study aims to investigate the association among coprescribed DOACs and antimicrobials and bleeding, cardiovascular disease and mortality. METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from January 1, 2011 to March 29, 2021. We used a cohort design to estimate hazard ratios (HRs) for bleeding outcomes (intracranial bleeding, gastrointestinal bleeding, other bleeding), comparing DOACs + clarithromycin/erythromycin/fluconazole users with DOACs users not receiving these antimicrobials. Cardiovascular outcomes were ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, and all-cause mortality. A 6-parameter case-crossover design comparing odds of exposure with different drug initiation patterns for all outcomes in hazard window vs referent window within an individual was also conducted. RESULTS: Of 483,815 DOAC users, we identified 21,701 coprescribed clarithromycin, 4532 coprescribed erythromycin, and 4840 coprescribed fluconazole. We observed an increased risk of gastrointestinal bleeding over 7 days following coprescription of DOAC + erythromycin vs DOAC alone (HR 3.66; 99% confidence interval [CI] 1.27-10.51), with wide CIs in case-crossover analysis. No evidence of increased risk of bleeding outcomes was seen for DOAC + clarithromycin/fluconazole in cohort and case-crossover analyses. For cardiovascular outcomes, compared with DOAC alone, an increased risk of cardiovascular mortality with DOAC + clarithromycin (HR 3.36; 99% CI 1.73-6.52) and increased risk of all-cause mortality with DOAC + clarithromycin/erythromycin/fluconazole were observed in cohort analysis. However, similar risks were found when initiating erythromycin/fluconazole with and without DOACs. CONCLUSION: We found no strong evidence of increased risks of bleeding and cardiovascular outcomes in DOACs + clarithromycin/fluconazole/erythromycin users except a possible short-term increased risk of gastrointestinal bleeding in DOACs + erythromycin users.