Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking. To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation. New-user, active-comparator, retrospective cohort study. A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019. Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706). The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding. 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio HR, 0.82 95% CI, 0.68 to 0.98; rate difference, 1.4 fewer events per 1000 person-years CI, 0.0 to 2.7). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1). Unmeasured confounding, incomplete laboratory data. In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban. Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.