Context: Recent trials have found that ximelagatran and warfarin are equally effective in stroke prevention for patients with atrial fibrillation. Because ximelagatran can be taken in a fixed, oral dose without international normalized ratio monitoring and may have a lower risk of hemorrhage, it might improve quality-adjusted survival compared with dose-adjusted warfarin. Objective: To compare quality-adjusted survival and cost among 3 alternative therapies for patients with chronic atrial fibrillation: ximelagatran, warfarin, and aspirin. Design: Semi-Markov decision model. Patients: Hypothetical cohort of 70-year-old patients with chronic atrial fibrillation, varying risk of stroke, and no contraindications to anticoagulation therapy. Main Outcome Measures: Quality-adjusted life-years (QALYs) and costs in US dollars. Results: For patients with atrial fibrillation but no additional risk factors for stroke, both ximelagatran and warfarin cost more than $50000 per QALY compared with aspirin. For patients with additional stroke risk factors and low hemorrhage risk, ximelagatran modestly increased quality-adjusted survival (0.12 QALY) at a substantial cost ($116000 per QALY) compared with warfarin. For ximelagatran to cost less than $50000 per QALY it would have to cost less than $1100 per year or be prescribed to patients who have an elevated risk of intracranial hemorrhage (>1.0% per year of warfarin) or a low quality of life with warfarin therapy. Conclusion: Assuming equal effectiveness in stroke prevention and decreased hemorrhage risk, ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin.