Background: Abnormal delayed electrograms (EGMs) from the anterior wall of the right ventricular outflow tract (RVOT) epicardium have become the ablation target in Brugada syndrome (BrS). Objective: The aim of this study was to analyze the safety, feasibility, and efficacy of a novel hybrid thoracoscopic approach to perform epicardial RVOT radiofrequency ablation in BrS. Methods: Thirty-six patients with BrS (26 men (72.2%); mean age 36.6±15.8 years; range 3–63 years) who underwent hybrid thoracoscopic epicardial ablation of RVOT from January 2016 to April 2018 were included in this study. Two expert electrophysiologists analyzed the EGMs during ajmaline challenge and guided the surgeon to perform ablation. Ajmaline challenge was repeated after 1 month to assess the absence of the BrS electrocardiographic pattern. Patients were followed by remote monitoring and outpatient visits every 6 months. Results: The elimination of all abnormal EGMs was achieved in 94.4% of patients. After a mean follow-up of 16 ± 8 months (range 6–30 months), freedom from ventricular arrhythmias was obtained in 7 (77.8%) patients in secondary prevention 9/36 (25%) and in 24 (100%) patients in primary prevention 24/36 (75%). Major complications were observed in 1 patient (2.8%), who experienced late cardiac tamponade. Conclusion: Hybrid thoracoscopic epicardial RVOT ablation in BrS is a safe and feasible approach, allowing direct visualization of ablation during radiofrequency delivery. Because of ventricular arrhythmia recurrences, implantable cardioverter-defibrillator implantation is still mandatory in patients treated in secondary prevention and with high risk.