OBJECTIVES: Estimate the lifetime costs and life-years (LYs) gained associated with stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) using novel oral anticoagulants (NOACs) apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg relative to warfarin. METHODS: A probabilistic Markov decision-analysis model was constructed to evaluate lifetime costs and LYs gained for patients receiving NOACs compared to patients receiving adjusted-dose warfarin. The modeled population was a hypothetical cohort of 70-year old patients with NVAF, at an increased risk for stroke (CHADS2≥ 1), with a renal creatinine clearance ≥ 50 mL/min, and no prior contraindications to anticoagulation. Rates for clinical events associated with drug efficacy and safety were estimated from the RE-LY (dabigatran 150 mg twice daily), ARISTOTLE (apixaban 5 mg twice daily), and ROCKET-AF (rivaroxaban 20 mg once daily) clinical trials. Medical costs were estimated from a societal perspective and were inflated to 2012 US dollars. Sensitivity analyses were conducted to determine influential model variables.  RESULTS: In the base case, warfarin had the lowest cost of $77,843 (standard deviation [SD]: $2,249), followed by rivaroxaban 20 mg ($78,683±$1,801), dabigatran 150 mg ($82,719±$1,905), and apixaban 5 mg ($85,350±$1,501). In contrast, warfarin had the highest estimated indirect costs ($25,485±$58), whereas the estimates were similar for apixaban ($9,499±$6), dabigatran ($9,497±$7), and rivaroxaban ($9,514±$6). Apixaban 5 mg yielded the highest number of LY’s gained, 13.76 (SD: 0.09), followed by dabigatran 150 mg (13.73±0.10), rivaroxaban 20 mg (13.48±0.10), and warfarin (12.98±0.06). The model results were dependent upon treatment costs and neurologic events associated with rivaroxaban 20 mg. CONCLUSIONS: In patients with NVAF, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg were more costly alternatives to warfarin but appear to result in a higher number of LYs gained.