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Background: The influence of different right ventricular lead locations on ventricular arrhythmias (VTA) in patients with a cardiac resynchronization therapy (CRT) is not clear. This study aimed to evaluate the influence on VTA in patients with a CRT when right ventricular lead was positioned at the right ventricular middle septum (RVMS) and the right ventricular apical (RVA). Methods: A total of 352 patients implanted with a CRT-defibrillator (CRT-D) between May 2012 and July 2016 in the Department of Cardiology of Anhui Provincial Hospital were included. Two-year clinical and pacemaker follow-up data were collected to evaluate the influence of the right ventricular lead location on VTA. Patients were divided into the RVMS group (n = 155) and the RVA group (n = 197) based on the right ventricular lead position. The VTA were compared between these two groups using a Kaplan-Meier curve and Cox multivariate analysis. Results: When the left ventricular lead location was not considered, RVMS and RVA locations did not affect VTA. However, the subgroup analysis results showed that when the left ventricular lead was positioned at the anterolateral cardiac vein (ALCV), the RVMS group had an increased risk of ventricular arrhythmias and appropriate defibrillation (hazard ratio [HR] = 3.29, P = 0.01 and HR = 4.33, P < 0.01, respectively); when the left ventricular lead was at the posterolateral cardiac vein (PLCV), these risks in the RVMS group decreased (HR = 0.45, P = 0.02 and HR = 0.33, P < 0.01, respectively), and when the left ventricular lead was at the lateral cardiac vein, there was no difference between the two groups. In regard to inappropriate defibrillation, there was no significant difference among all these groups. Conclusions: When the left ventricular lead was positioned at ALCV or PLCV, the right ventricular lead location was associated with VTA and appropriate defibrillation after CRT. Greater distances between leads not only improved cardiac function but also may reduce the risk of VTA. Key words: Cardiac Resynchronization Therapy; Heart Failure; Ventricular Remodeling; Ventricular Arrhythmias