Objective: The primary objective of this study was to estimate the long-term cost-effectiveness of stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the United States using new anticoagulant therapies - dabigatran 150 mg, apixaban 5 mg, and rivaroxaban 20 mg - as well as the standard treatment, warfarin. Methods: A Markov decision-analysis model was constructed using data from clinical trials that evaluated the new oral anticoagulants relative to warfarin (apixaban 5 mg & ARISTOTLE, dabigatran 150 mg & RE-LY, and rivaroxaban 20 mg & ROCKET-AF) to compare the lifetime cost and quality-adjusted life expectancy. The Markov model target population was a hypothetical cohort of 70-year old patients with nonvalvular atrial fibrillation, an increased risk for stroke (CHADS₂ ≥ 1, or equivalent), a renal creatinine clearance (CrCl) of 50 or above, and no contraindication to anticoagulant therapy. Using pair-wise comparisons of each therapy, analyses were conducted to evaluate incremental cost-effectiveness ratios (ICERs), net monetary benefits (NMBs), lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results: In the base case, warfarin had the lowest cost of $71,857 (95% confidence interval [CI]: $68,730, $77,452), followed by rivaroxaban 20 mg ($74,023; 95% CI: $70,943, $77,307), dabigatran 150 mg ($78,584; 95% CI: $75,277, $81,968), and apixaban 5 mg ($81,180; 95% CI: $78,642, $83,756). Apixaban 5 mg also yielded the highest QALY estimate, 8.63 (95% CI: 8.52, 8.72), followed by dabigatran 150 mg (8.55; 95% CI: 8.43, 8.67), rivaroxaban 20 mg (8.42; 95% CI: 8.31, 8.54), and warfarin (8.17; 95% CI: 8.1, 8.24). In a Monte Carlo probabilistic sensitivity analysis, apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg, and warfarin were cost effective in 45%, 37%, 19%, 0%, respectively, of the simulations using a willingness-to pay threshold of $50,000 per QALY gained. From the one-way sensitivity analyses, new anticoagulant (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) costs and probabilities associated with intracranial hemorrhage and stroke for patients receiving rivaroxaban 20 mg were identified as significant influential variables impacting model results. Conclusion: In patients with NVAF and an increased risk of stroke prophylaxis, apixaban 5 mg, dabigatran 150 mg, and rivaroxaban 20 mg may all be cost-effective alternatives to warfarin depending on pricing in the United States and neurologic events for rivaroxaban 20 mg.