Cardiac resynchronization therapy (CRT) is an effective treatment for selected heart failure (HF) patients. Although transvenous implantation is the standard method, it is not feasible in some patients, so the epicardial lead emerges as an alternative. We aim to compare CRT response, procedure-related complications, and the occurrence of clinical outcomes between patients with transvenous and epicardial leads. In a single-center retrospective study, we enrolled consecutive HF patients submitted to CRT implantation with a defibrillator between 2013 and 2022. Clinical response was defined as an improvement of at least one of the New York Heart Association classes with no occurrence of cardiovascular death or HF hospitalization in the first year of follow-up. Echocardiographic response was attained with an increase in left ventricular ejection fraction 10% or a reduction of left ventricular end-diastolic volume >15% at 6-12 months after CRT implantation. Major adverse cardiovascular events (MACE) (cardiovascular mortality and HF hospitalization) and all-cause mortality were evaluated. From a total of 149 patients, 38% (n=57) received an epicardial lead. Clinical (63% versus 60%, p=0.679) and echocardiographic (63% versus 60%, p=0.679) responses were similar between the transvenous and epicardial groups. Patients in the transvenous group had a shorter hospital stay (2 versus 7 days, p<0.001). Procedure-related complications were comparable between groups (24% versus 28%, p=0.572), but left ventricular lead-related complications were more frequent in the transvenous group (14% versus 2%). During a median follow-up of 4.7 years, the rate of MACE was 30% (n=44), with no differences in both groups (p=0.591), neither regarding HF hospitalization (p=0.917) nor cardiovascular mortality (p=0.060). Nevertheless, the epicardial group had a higher rate of all-cause mortality (35% versus 20%, p=0.005), the majority occurring during long-term follow-up (>12 months), with no deaths in the postoperative period. Considering the comparable rates of CRT response, procedure-related complications, and MACE between groups, we conclude that epicardial lead is a feasible alternative for CRT when transvenous lead implantation is not possible. The occurrence of a higher number of all-cause deaths in epicardial patients in the long-term follow-up was mainly due to infectious complications (unrelated to the lead) and the progression of oncological/chronic diseases.