OBJECTIVES: Direct oral anticoagulants (DOACs) are commonly co-prescribed with digoxin, but whether there is a drug interaction between them is unclear. We aimed to investigate potential drug interactions between DOACs and digoxin. STUDY DESIGN AND SETTING: We identified DOAC users during January 1, 2011-December 31, 2019 using data from Clinical Practice Research Datalink Aurum in cohort design with propensity score to compare the hazards of effectiveness cardiovascular and mortality outcomes and safety bleeding outcomes, respectively, in DOAC + digoxin users versus DOAC + beta-blocker users. A case-crossover design was conducted to compare odds of exposure to different drug initiation patterns in hazard period versus referent period. RESULTS: Of 397,459 DOAC users, we identified 25,251 co-prescribed digoxin and 109,779 co-prescribed beta-blockers in cohort study. A lower proportion of DOAC + digoxin users were men (46%) in contrast with that of DOAC + beta-blocker users (53%). Mean age of DOAC + digoxin users (77.1 years) were higher than DOAC + beta-blocker users (74.5 years). No increased risk of pharmacologically predictable DOAC safety outcomes or specific effectiveness outcomes was seen with DOAC + digoxin. A higher risk of all-cause mortality (hazard ratio: 1.35; 99% confidence interval [CI]: 1.14-1.61) was observed with DOAC + digoxin versus DOAC + beta-blockers. In the case-crossover study, a 24% higher odds of all-cause mortality was seen with initiating digoxin while taking DOAC (odds ratio: 1.24; 99% CI: 1.06-1.45); and a 63% higher odds was also seen with initiating DOAC while taking digoxin (odds ratio: 1.63; 99% CI: 1.41-1.88). CONCLUSION: We found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. Future work is recommended to investigate the underlying mechanism of association with all-cause mortality. PLAIN LANGUAGE SUMMARY: This study aimed to examine potential drug interactions between direct oral anticoagulants (DOACs) (a drug class to prevent blood clots) and digoxin (treatment of abnormal heart rhythms). We compared a range of clinical outcomes in people prescribed DOAC and digoxin with people prescribed DOAC and beta-blockers (a treatment alternative to digoxin). We also used a new study design (case-crossover design) to compare the risk of clinical outcomes between different periods within a person as a validation. In both study designs, we found no increased risk of bleeding when DOACs are used with digoxin, suggesting combined use does not lead to drug-drug interaction. However, we found an increased risk of all-cause death associated with digoxin in DOAC users which requires further investigation.