This ARISTOPHANES analysis examined stroke/systemic embolism (SE) and major bleeding (MB) among a subgroup of nonvalvular atrial fibrillation (NVAF) patients with obesity prescribed warfarin or non-vitamin K antagonist oral anticoagulants (NOACs) in order to inform clinical decision making. A retrospective observational study was conducted among NVAF patients who were obese and initiated apixaban, dabigatran, rivaroxaban, or warfarin from 1 January 2013–30 September 2015, with data pooled from CMS Medicare and four US commercial claims databases. Propensity score matching was completed between NOACs and against warfarin in each database, and the results were pooled. Cox models were used to evaluate the risks of stroke/SE and MB. A total of 88,461 patients with obesity were included in the study. Apixaban and rivaroxaban were associated with a lower risk of stroke/SE vs. warfarin (HR: 0.63, 95% CI: 0.49–0.82 and HR: 0.84, 95% CI: 0.72–0.98). Dabigatran was associated with a similar risk of stroke/SE compared to warfarin. Compared with warfarin, apixaban and dabigatran had a lower risk of MB (HR: 0.54, 95% CI: 0.49–0.61 and HR: 0.75, 95% CI: 0.63–0.91). Rivaroxaban was associated with a similar risk of MB compared to warfarin. In this high-risk population with obesity, NOACs had a varying risk of stroke/SE and MB vs. warfarin.