Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HC) and predicts adverse outcome. Radiofrequency catheter ablation (RFCA) represents a potentially advantageous alternative to lifelong pharmacologic treatment. However, its efficacy in patients with HC is not established. In the present study, the feasibility, safety, and efficacy of RFCA of AF in patients with HC were evaluated. Twenty-six patients with HC with paroxysmal (n = 13) or permanent (n = 13) AF refractory to antiarrhythmic therapy (age 58 +/- 11 years, time from AF onset 7.3 +/- 6.2 years, left atrial volume 170 +/- 48 ml) underwent RFCA. A schema with pulmonary vein isolation plus linear lesions was used. No major periprocedural complication occurred. One patient died from a hemorrhagic stroke 4 weeks after RFCA while in sinus rhythm. During a 19 +/- 10-month follow-up, 9 of the remaining 25 patients (36%) experienced recurrence of AF (despite repeated RFCA in 3) and were considered failures, whereas 16 remained in sinus rhythm (i.e., 64% overall success rate). Ten of these 16 patients were off antiarrhythmic drug therapy at final evaluation. RFCA was highly successful in patients with paroxysmal AF (77% success rate compared with 50% in the subgroup with permanent AF). Patients with restoration of sinus rhythm showed marked symptomatic improvement (final New York Heart Association functional class 1.2 +/- 0.5 vs 1.7 +/- 0.7 before the procedure, p = 0.003). Conversely, patients for whom RFCA failed showed no change (final functional class 1.9 +/- 0.8 vs 1.7 +/- 0.9 before the procedure, p = 0.59). In conclusion, in most studied patients with HC, RFCA proved a safe and effective therapeutic option for AF, improved functional status, and was able to reduce or postpone the need for long-term pharmacologic treatment.