Background-In comparison to warfarin, non-vitamin K antagonist oral anticoagulants (NOACs) have the advantages of ease of dosing, fewer drug interactions, and lack of need for ongoing monitoring. We sought to evaluate whether these advantages translate to improved adherence and whether adherence is associated with improved outcomes in patients with atrial fibrillation. Methods and Results-We performed a retrospective cohort analysis by using a large US commercial insurance database to identify 64 661 patients with atrial fibrillation who initiated warfarin, dabigatran, rivaroxaban, or apixaban treatment between November 1, 2010, and December 31, 2014. During a median of 1.1 y of follow-up, 47.5% of NOAC patients had a proportion of days covered of ≥80%, compared with 40.2% in warfarin patients (P < 0.001). Patients with CHA2DS2-VASc (risk based on the presence of congestive heart failure, hypertension age 65-74 y, age ≥75 y, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, sex category) score ≥4 were at increased risk of stroke when they were not taking anticoagulation < 1 month versus <1 week (1-3 months: hazard ratio [HR] 1.96, 3-6 months: HR 2.64, ≥6 months: HR 3.66; all P ≤ 0.001). Patients with CHA2DS2-VASc score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≤6 months (HR 2.73, P < 0.001). In these patients with CHA2DS2-VASc score ≥2, nonadherence was not associated with intracranial hemorrhage. Among patients with CHA2DS2-VASc score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding. Conclusions-Adherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA2DS2-VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA2DS2-VASc score 0 or 1.