BACKGROUND: Radiofrequency catheter ablation of atrial fibrillation (AF) guided by complex fractionated atrial electrograms has been reported to eliminate AF in a large proportion of patients. However, only a small number of patients with chronic AF have been included in previous studies. METHODS AND RESULTS: In 100 patients (mean age, 57+/-11 years) with chronic AF, radiofrequency ablation was performed to target complex fractionated atrial electrograms at the pulmonary vein ostial and antral areas, various regions of the left atrium, and the coronary sinus until AF terminated or all identified complex fractionated atrial electrograms were eliminated. Ablation sites consisted of > or = 1 pulmonary vein in 46% of patients; the left atrial septum, roof, or anterior wall in all; and the coronary sinus in 55%. During 14+/-7 months of follow-up after a single ablation procedure, 33% of patients were in sinus rhythm without antiarrhythmic drugs, 38% had AF, 17% had both AF and atrial flutter, 9% had persistent atrial flutter, and 3% had paroxysmal AF on antiarrhythmic drugs. A second ablation procedure was performed in 44% of patients. Pulmonary vein tachycardia was found in all patients in both previously targeted and nontargeted pulmonary veins. There were multiple macroreentrant circuits in the majority of patients with atrial flutter. At 13+/-7 months after the last ablation procedure, 57% of patients were in sinus rhythm without antiarrhythmic drugs, 32% had persistent AF, 6% had paroxysmal AF, and 5% had atrial flutter. CONCLUSIONS: Modest short-term efficacy is achievable with radiofrequency ablation of chronic AF guided by complex fractionated atrial electrograms, but only after a second ablation procedure in > 40% of patients. Rapid activity in the pulmonary veins and multiple macroreentrant circuits are common mechanisms of recurrent atrial arrhythmias.