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BACKGROUND Pulmonary vein isolation (PVI) is a cornerstone ablation strategy in the management of patients with atrial fibrillation (AF). Consensus guidelines and statements recommend PVI during the index catheter ablation procedure in patients with paroxysmal and persistent AF. OBJECTIVE The objective of this analysis was to evaluate patients with persistent and long-standing persistent AF who were treated with the cryoballoon ablation catheter by PVI technique. METHODS Consecutive patients with drug-refractory symptomatic persistent and long-standing persistent AF who underwent cryoballoon catheter ablation by a PVI-only procedure were prospectively included in this single-arm multicenter evaluation. Data on procedural characteristics, safety, and long-term freedom from AF recurrence were analyzed. RESULTS Four hundred eighty-six subjects (mean age 60.8 ± 9.3 years; 389 (80%) men; 434 (89.3%) with persistent AF; 52 (10.7%) with long-standing persistent AF; left atrial diameter 44.6 ± 6.2 mm) underwent cryoballoon ablation in 35 Italian centers. The mean procedure time (skin-to-skin) was 109.9 ± 52.9 minutes, and the mean fluoroscopy time was 29.6 ± 14.5 minutes. Periprocedural complications were observed in 21 subjects (4.3%), and the acute PVI success rate was 97.6% across all patients. Using a 90-day blanking period, the single procedure Kaplan-Meier estimates of AF event-free survival were 63.9% at 12 months and 51.5% at 18 months. CONCLUSION In this multicenter evaluation of cryoballoon ablation, the PVI procedure was safe, effective, and efficient with regard to the treatment of patients with persistent and long-standing persistent AF. The reasonable mid-term success rates agree with current clinical studies that establish PVI as a cornerstone index ablation strategy.