Background Despite the use of two crossed Perclose ProGlide™ (Abbott Vascular Devices) is the most widespread technique to close the main arterial access in transfemoral transcatheter aortic valve implantation (TF‐TAVI), the safest and most effective strategy still remains much debated. Aims The aim of the present study was to evaluate the performance of a single Perclose ProGlide suture‐mediated closure device to obtain femoral hemostasis after sheathless implantation of self‐expanding transcatheter heart valves through their 14 F‐equivalent fix delivery systems. Methods This prospective observational study included 439 patients undergoing TF‐TAVI at the “Montevergine” Clinic of Mercogliano, Italy. All patients underwent hemostasis of the large‐bore access using a single Perclose ProGlide with preclose technique, after sheathless implantation of self‐expanding transcatheter heart valves through 14 F‐equivalent fix delivery systems. A multidetector computed tomography analysis of size, tortuosity, atherosclerotic, and calcification burdens of the ilio‐femoral access route was made by a dedicated corelab. Vascular complications (VCs), percutaneous closure device (PCD) failure, and bleedings were adjudicated by a clinical events committee. Results A total of 81 different VCs were observed in 60 patients (13.7%); among these, 41 (5% of patients) were categorized as major. PCD failure occurred in 14 patients (3.2%). At the logistic regression analysis, no predictors of PCD failure have been identified. Conclusion This registry suggests that the use of a single suture‐mediated closure device could be considered a safe and efficient technique to achieve access site hemostasis in patients undergoing TF‐TAVI through 14 F‐equivalent fix delivery systems.