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Background: Persistent left superior vena cava (PLSVC) is a rare venous anomaly, affecting 0.3-0.5% of the general population. Cardiac resynchronization therapy (CRT) implantation in patients with PLSVC is challenging due to a complex anatomy. Moreover, data on CRT implantation in this patient population is scarce. Our aim was to report a series of patients with PLSVC and CRT implantation focusing on challenges and pitfalls., Methods: Electronic medical databases on patients with CRT implantation at the University Heart Centers in Zurich, Switzerland, and Lübeck, Germany, were screened for individuals with a PLSVC. Clinical and demographic characteristics as well as procedural data were reported in all patients., Results: This study presents six cases with a median age of 66 years. CRT implantation was successful in five patients, leading to a reduced QRS duration and improved left ventricular ejection fraction. Atrial fibrillation, ischemic cardiomyopathy, valvular heart disease, and dilated cardiomyopathy were observed in this group as underlying conditions. Specialized tools, such as active fixation left ventricular leads, were utilized. One patient experienced major complications., Conclusions: This case series shows that although challenging, conventional endovascular CRT implantation is feasible in PLSVC patients. Specialized tools for visualization and fixation may help. Our experiences highlight the importance of preprocedural evaluation of the anatomy and precise intervention planning., (© 2024. The Author(s).)