Our study examined the impact of adherence to novel oral anticoagulants [NOACs - dabigatran and rivaroxaban] on ischemic-stroke (IS), major-bleeding (MB), deep-vein-thrombosis and pulmonary-embolism (DVTPE) risk in a large, nationwide, propensity-matched sample.A retrospective cohort study utilized data from a US commercial managed-care database (2010-2012). Adult patients with ≥1 diagnosis of atrial fibrillation/flutter (ICD-9 427.31/32),1 prescription of NOACs and CHAA total of 3,629 and 1,946 patients with at least 6 and 12 months of NOAC use were included. Based on a PDC threshold of ≥80%, adherence rates at 6 and 12 month usage were 77% and 76%, respectively. Patients with lowest adherence were from the South, had low stroke risk and EPO/HMO insurance. Using Cox models with matched cohorts, nonadherence within the first 6 months' use was significantly associated with higher risk of IS and DVTPE (IS: hazard ratio [HR] = 1.82, p = .002; DVTPE: HR = 2.12, p = .010) and the risk increased with nonadherence for the prolonged period of 12 months' use (IS: HR = 2.08, p = .022; DVTPE: HR = 5.39, p = .003). The risk of MB was not different (p .05) between adherent and nonadherent groups for both 6 month and 12 month cohorts.Adherence to NOACs for both 6 months and prolonged use (up to 12 months) was associated with a reduction in IS and DVTPE risk, but did not substantially increase risk of MB. Further studies on newer, individual NOACs and older populations are warranted.