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OBJECTIVES Hybrid ablation of atrial fibrillation (AF) is a promising treatment strategy; however, data regarding its efficacy and safety are still limited. METHODS Patients with non-paroxysmal AF were enrolled. First, a thoracoscopic, epicardial isolation of pulmonary veins and the left atrial posterior wall ('box lesion') was performed; a novel unipolar/bipolar radiofrequency device was used. Moreover, in 12 patients enrolled thereafter, the left atrial appendage was occluded. Electrophysiological evaluation and catheter ablation were performed 2-3 months later, with the goal of verifying or completing (if needed) the box lesion and ablation of the ganglionated plexi and the cavotricuspid isthmus. Outcomes were assessed using 1-week and 24-h Holter monitoring, repeated echocardiography and laboratory measurements. RESULTS Thirty-eight patients (13 persistent and 25 long-standing persistent AF) were enrolled with a mean AF duration of 33 ± 32.9 months. The procedure was successfully completed in 35 patients; 3 patients underwent only the surgical part because of a postoperative left atrial appendage thrombus (2 patients) and perioperative stroke (1 patient). After 6 months, 30 (86%) patients were arrhythmia-free, whereas 80% were also off antiarrhythmics. After 1 year, 28 (82%) patients were arrhythmia-free, 79% were off anti-arrhythmics and 47% were off anticoagulation treatment. Four (10.5%) serious postoperative complications occurred, including 1 stroke, 1 right phrenic nerve palsy and 2 pneumothoraxes with a need for drainage. Significant improvements were observed in echocardiographic, functional and serological parameters. CONCLUSIONS Hybrid ablation is an effective treatment strategy for patients with persistent or long-standing persistent AF. Over 80% of patients were arrhythmia-free 1 year after the procedure. Sinus rhythm restoration was accompanied by improvements in functional, echocardiographic and serological markers.