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Background: Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population. Objectives: This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods: This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013‐30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score‐matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB. Results: Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55–0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72–0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57–0.66) and dabigatran (HR: 0.79, 95% CI: 0.70–0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08–1.21) was associated with a higher risk vs warfarin. Conclusion: Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real‐world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population. [ABSTRACT FROM AUTHOR]