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: To investigate the association between co-prescribed DOACs and antimicrobials and bleeding, cardiovascular disease and mortality. METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from 1/1/2011-29/3/2021. We used a cohort design to estimate hazard ratios 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 to different drug initiation patterns for all outcomes in hazard window versus referent window within an individual was also conducted. RESULTS: Of 483,815 DOAC users, we identified 21,701 co-prescribed clarithromycin, 4,532 co-prescribed erythromycin and 4,840 co-prescribed fluconazole. We observed an increased risk of gastrointestinal bleeding over 7-days following co-prescription of DOAC+erythromycin versus DOAC alone (HR:3.66; 99%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 DOAC. 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.