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Background: Radiofrequency catheter ablation (RFA) has emerged as an important treatment strategy for atrial fibrillation (AF). The potential cost-effectiveness of RFA for AF, relative to antiarrhythmic drug (AAD) therapy, has not been fully explored from a US perspective.Methods and Results: We constructed a Markov disease simulation model for a hypothetical cohort of patients with drug-refractory paroxysmal AF, treated either with RFA with/without AAD or AAD alone. Costs and quality-adjusted life-years were projected over 5 years. Model inputs were drawn from published clinical trial and registry data, from new registry and trial data analysis, and from data prospectively collected from patients with AF treated with RFA at our institution. We assumed no benefit from ablation on stroke, heart failure or death, but did estimate changes in quality-adjusted life expectancy using data from several AF cohorts. In the base case scenario, cumulative costs with the RFA and AAD strategies were $26,584 and $19,898, respectively. Over 5 years, quality-adjusted life expectancy was 3.51 quality-adjusted life-years with RFA versus 3.38 for the AAD group. The incremental cost-effectiveness ratio for RFA versus AAD was thus $51,431 per quality-adjusted life-year. Model results were most sensitive to time horizon, the relative utility weights of successful ablation versus unsuccessful drug therapy, and to the cost of an ablation procedure.Conclusions: RFA with/without AAD for symptomatic, drug-refractory paroxysmal AF appears to be reasonably cost-effective compared with AAD therapy alone from the perspective of the US health care system, based on improved quality of life and avoidance of future health care costs. [ABSTRACT FROM AUTHOR]