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Aims: This prospective clinical trial was designed to evaluate the efficacy of an ablation strategy, namely '2C3L', in the treatment of persistent atrial fibrillation (AF); and to compare its efficacy with that of the 'stepwise' approach, which has been acknowledged as a promising ablation technique for persistent AF.Methods and Results: The '2C3L' technique is a fixed ablation approach consisting of bilateral circumferential pulmonary vein antrum isolation (PVAI) and three linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavo-tricuspid isthmus. One hundred and forty-six patients with persistent AF were randomized to undergo ablation by using the '2C3L' or the 'stepwise' technique (n = 73, respectively). The primary endpoint was freedom from any atrial tachyarrhythmia off antiarrhythmic drug (AAD) after a single procedure at follow-up. Twelve months after a single procedure, there was no difference in sinus rhythm (SR) maintenance rate between the two groups (67% for '2C3L' vs. 60% for 'stepwise', P = 0.394; 95% confidence interval of between-group difference -8.7 to 22.4%). The procedure (222 ± 42 vs. 263 ± 41 min), fluoroscopy (41 ± 9 vs. 55 ± 8 min), and radiofrequency (RF) (107 ± 32 vs. 128 ± 38 min) time were significantly shorter in the '2C3L' group (all P < 0.001). At 25 ± 5 months after the first procedure, 57.5 and 52.1% of patients from the '2C3L' group and the 'stepwise' group were in SR off AAD (P = 0.494), respectively.Conclusions: For catheter ablation of persistent AF, the '2C3L' strategy is a fixed approach associated with clinical efficacy similar to that of the 'stepwise' approach but with less RF delivery, fewer X-ray exposure, and shorter procedural time. [ABSTRACT FROM AUTHOR]