ABSTRACT Background Large vegetations in cardiac implantable electronic devices (CIEDs) are associated with high mortality due to risks of major pulmonary artery obstruction. The rising incidence of CIEDs infections has complicated management, particularly in patients with delayed diagnoses. Current guidelines recommend open‐heart surgery for vegetations > 2.5 cm, but this approach poses significant risks for high‐morbidity patients. This study evaluates the feasibility and outcomes of percutaneous vacuum‐assisted aspiration using the AngioVac system in managing giant vegetations (≥ 4.0 cm) in patients unsuitable for open surgery. Materials and Methods Fourteen patients with giant vegetations (≥ 4.0 cm), undergoing transvenous lead extraction, were treated with the AngioVac system. The procedure involved large‐bore central venous cannulation and extracorporeal aspiration of vegetations. Outcomes assessed included procedural success, embolization management, and post‐extraction microbiological findings. Results The cohort included 64% males with a median age of 73 years. Vegetation sizes ranged from 4.0 to ≥ 7.0 cm. Most patients (79%) presented with advanced heart failure symptoms (NYHA class III/IV). Despite pulmonary embolism in 29% of cases, all were successfully managed with mechanical aspiration. The procedure achieved 100% complete removal of all leads and vegetations, with no perioperative mortality, and all patients were discharged alive. Conclusion Percutaneous aspiration using the AngioVac system is a safe and effective alternative to open‐heart surgery for high‐risk patients with giant vegetations. This minimally invasive approach demonstrates potential for broader application in managing high‐risk CIEDs infections, warranting further investigation in larger studies.