Aims There is an increasing trend evaluating the role of non-pulmonary vein (PV) triggers to improve ablation outcomes in persistent atrial fibrillation (AF) as pulmonary vein isolation (PVI) strategy alone has modest outcomes. We investigated the long-term safety and efficacy of left atrial appendage isolation (LAAi) in addition to PVI using cryoballoon (CB) in persistent AF. Methods and results In this multicentre retrospective analysis, we included a total of 193 persistent AF patients (mean age: 60 +/- 11 years, 50.3% females) who underwent PVI and LAAi using CB. Baseline and follow-up data including electrocardiography (ECG), 24 h Holter ECGs, and echocardiography were recorded for all patients. Atrial tachyarrhythmia (ATa) recurrence was defined as the detection of AF, atrial flutter, or atrial tachycardia (>= 30 s) after a 3-month blanking period. At a median follow-up of 55 (36.5-60.0) months, 85 (67.9%) patients with PVI + LAAi were in sinus rhythm after the index procedure. Ischaemic stroke/transient ischemic attack occurred in 14 (7.2%) patients at a median of 24 (2-53) months following catheter ablation. Multivariate regression analysis revealed heart failure with preserved ejection fraction [hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.04-5.02; P = 0.038], male gender (HR 0.53, 95% CI 0.29-0.96; P = 0.037), and LA area (HR 1.04, 95% CI 0.53-1.32; P = 0.023) as independent predictors of ATa recurrence. Conclusion Our findings demonstrated that the LAAi + PVI strategy using CB had acceptable long-term outcomes in patients with persistent AF. Systemic thrombo-embolic events are an important concern throughout the follow-up, which were mostly observed in case of non-adherence to anticoagulants.