Abstract Background Transvenous lead extraction (TLE) has become an established therapy for patients with cardiac device-related complications such as infection or lead dysfunction. Although safe and effective, periprocedural complications such as vascular or cardiac lacerations with the need for major surgical intervention occur and lead to morbidity and mortality. Objective & Methods The aim of this study was to conduct a retrospective analysis of the incidence, management and outcome of all major complications suffered by patients undergoing TLE in the GALLERY and to compare patient characteristics, procedural data and outcome against patients who suffered minor or no periprocedural complications. We performed multivariate regression analysis to identify independent predictors for death in patients with major complications. Results We identified 52 patients with major (Group A), 57 patients with minor (Groups B) and 2415 patients with no periprocedural complications (Group C) undergoing TLE in the GALLERY (2.1%, 2.3% and 95.7% of total patients, respectively). There were no differences in age (67.4±14.0 vs. 66.6±13.5 vs. 68.1±13.8 years; p=0.612), body mass index (BMI – 26.5±5.4 vs. 26.1±4.2 vs. 27.1±4.7 kg/m2; p=0.140) or other comorbidities, such as arterial hypertension or chronic kidney disease (CKD), except for more patients with diabetes mellitus (15.4 vs. 42.1 vs. 31.3%; p=0.01) in Group B and a trend towards less patients with previous cardiac surgery (15.4 vs. 35.1 vs. 24.2%; p=0.053) in Group A. Mean number of leads per patient were 2.5±1.1, 2.4±1.0 and 2.4±1.0 (p=0.645). Most common minor complication was pocket hematoma in 82.6% of cases. Laceration of the superior vena cava (SVC – 40.4%) was the most common major complication, followed by perforation of the right atrium (RA – 23.1%). Emergent median sternotomy was necessary in 80.8% of cases in Group A, of which 67.4% required cardiopulmonary bypass. Clinical success for TLE could only be achieved in 63.5% of cases in Group A, whereas Groups B and C achieved 100.0 and 98.5% (p<0.001), respectively. The mortality rate in Group A was 28.9%, in contrast to 5.3% and 3.0% in Groups B and C (p<0.001), which translates into a procedure-related mortality of 0.6% for the entire GALLERY. Septic shock was the most common cause of death in all groups (7.7 vs. 3.5 vs. 1.9%, p=0.013). Multivariate regression analysis revealed CKD (OR:4.7, 95%CI: 1.06-20.7, p=0.04) and previous cardiac surgery (OR:6.3, 95%CI: 1.2-33.6, p=0.03) as independent predictors for death in patients who suffered a major complication during TLE. Conclusion Although rare, TLE remains a procedure with potential for major complications such as lacerations of the SVC or perforation of the RA. Immediate availability of emergent surgical intervention ensures a survival rate of 71,1%. Previous cardiac surgery and CKD seem to be independent predictors for death in such patients.