BACKGROUND: Direct oral anticoagulants (DOACs) are commonly co-prescribed with statins. Although biologically plausible, whether there is a drug interaction between DOACs and atorvastatin/simvastatin is unclear. AIM: To investigate the association between co-prescribed DOACs and atorvastatin/simvastatin and bleeding, cardiovascular disease, and mortality. DESIGN AND SETTING: Cohort and case-crossover study using data from English general practices in the Clinical Practice Research Datalink Aurum from 1 January 2011 to 31 December 2019. METHOD: A cohort design was used to estimate hazard ratios for clinically relevant pharmacological interaction safety outcomes (intracranial bleeding, gastrointestinal bleeding, and other bleeding) comparing DOACs and atorvastatin/simvastatin with DOACs and other statins (fluvastatin, pravastatin, and rosuvastatin that are not anticipated to interact with DOACs). Effectiveness outcomes (ischaemic stroke, myocardial infarction, venous thromboembolism, cardiovascular mortality, and all-cause mortality) were also included. In addition, a case-crossover design was used to compare the odds of exposure to different drug initiation patterns in the hazard window versus the referent window within an individual. RESULTS: Of 397 459 patients who were prescribed DOACs, 70 318 people co-prescribed atorvastatin and 38 724 co-prescribed simvastatin were selected. The cohort analysis showed no difference in risk of all outcomes comparing patients prescribed DOACs and atorvastatin/simvastatin versus those prescribed DOACs and other statins. In the case-crossover analysis, odds ratios (ORs) for other bleeding (OR 5.06, 99% confidence interval [CI] = 3.79 to 6.76) among those initiating DOACs while taking atorvastatin and the ORs for gastrointestinal bleeding (OR 6.05, 99% CI = 4.28 to 8.54) and other bleeding (OR 6.81, 99% CI = 4.74 to 9.78) among those initiating DOACs while taking simvastatin were greater than those initiating DOAC monotherapy. Similar patterns were also observed for cardiovascular mortality and all-cause mortality. CONCLUSION: This study shows no evidence of interaction between DOACs and atorvastatin/simvastatin. However, people starting a DOAC while taking atorvastatin/simvastatin were at high risk of bleeding and mortality, likely because of temporal clinical vulnerability.