Background: Currently available second-generation cryoballoon (CB2) is accepted as an effective and safe tool for pulmonary vein isolation (PVI). Although much more data exist about 1-year outcomes of CB2 ablation, data on long-term outcomes are scarce. Objective: We aimed to assess the long-term outcomes of PVI using CB2 in a large-scale symptomatic atrial fibrillation (AF) population at our tertiary referral center. Methods: In this nonrandomized prospective observational study, a total of 486 patients with paroxysmal (71%) or persistent (29%) AF who underwent index PVI using CB2 at our hospital between January 2013 and June 2017 were enrolled. Atrial tachyarrhythmia (ATa)-free survival was defined as the absence of AF, atrial flutter, or atrial tachycardia recurrence ≥30 s following a 3 months blanking period. Predictors of recurrence were evaluated by univariate and multivariate Cox proportional hazards regression models. Results: Acute procedural success rate was 99.8% (1898/1902 PVs). Mean procedural and fluoroscopy time were 64.9 ± 9.2 and 12.1 ± 2.6, respectively. At median 39 (interquartile range: 26-56) months follow-up, ATa-free survival was 78.6% after a single procedure (280/345 [81.2%] for paroxysmal AF vs. 102/141 [72.3%] for persistent AF, P =.019) and 84.4% after a mean 1.48 ± 0.42 ablations. Cox regression analysis showed that left atrium diameter, duration of AF history, and early ATa recurrence were found as the independent predictors of late recurrence. Phrenic nerve palsy was observed in 17 (3.5%) patients. Conclusions: CB2-based PVI is effective to maintain sinus rhythm in a significant proportion of paroxysmal and persistent AF patients with an acceptable complication rate at long-term follow-up.