Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Medtronic, Inc. OnBehalf Cryo AF Global Registry Investigators Background Since introduced in Europe over 15 years ago, cryoballoon ablation for the treatment of patients with atrial fibrillation (AF) has proven to be safe and effective. Purpose Report on patient and procedural characteristics, ablation techniques, and outcomes. Also, determine the independent predictors of a procedural adverse event in real-world usage. Methods Patients with AF were enrolled in the prospective, multicenter Cryo AF Global Registry (NCT02752737) and treated with cryoballoon ablation at 38 European centers according to standard-of-care. The primary efficacy endpoint was freedom from a ≥30 sec episode of AF/atrial flutter (AFL)/atrial tachycardia (AT) at 12-months. The primary safety endpoint was the rate of serious adverse events related to the device and/or procedure. Univariate and multivariable models identified baseline patient and procedural characteristics that predicted a serious procedure-related complication. Results: Of 1,418 subjects who completed an index procedure, the cohort was 62 ± 11 years of age, 37.7% female, and 72.2% paroxysmal AF (PAF). In total, 32.2% of patients were treated with cryoablation as a first-line therapy. Non-general anesthesia was used in 76.0% of procedures. Ablation adjunctive to the cryoballoon pulmonary vein isolation was applied in few cases: 2.0% of patients were treated with a cavotricuspid isthmus (CTI) line with focal radiofrequency ablation and 0.8% of patients received other non-PVI ablation. The mean procedure, left atrial dwell, and fluoroscopy times were 81 ± 34, 54 ± 25, and 14 ± 13 minutes, respectively. Among the 766 patients with 12-month follow-up, freedom from AF/AFL/AT recurrence ≥30 sec was 83.3% (95% CI: 79.8-86.3%) and 71.6% (95% CI: 64.6-77.4%) in patients with PAF and persistent AF, respectively. The serious procedure- and device-related adverse event rates were 4.7% and 2.0%, respectively. Female sex was significantly associated with the occurrence of an adverse event in univariate analysis (P < 0.05), but (after accounting for patient age and NYHA status) no baseline patient characteristic independently predicted a procedure-related adverse event. However, prolonged procedure duration (OR = 1.01 (95% CI: 1.00-1.01)), use of general anesthesia (OR = 1.71 (95% CI: 1.01 – 2.92)), and delivery of a CTI line (OR = 3.04 (95% CI: 1.01-9.20) were each independently associated with the occurrence of a serious procedural safety event (all P < 0.05). Conclusion: Cryoablation treated patients across the AF disease spectrum with one-third of patients treated prior to antiarrhythmic drug usage and another third treated for persistent AF. The results indicate extra diligence is warranted in patients under general anesthesia and for those who receive adjunctive CTI ablation. Cryoballoon ablation is consistently safe for patients independent of baseline patient characteristics and comorbidities in real-world use.