Thoracic transplantation is considered for patients with Eisenmenger syndrome (ES) who have refractory right ventricular failure despite optimal therapy for pulmonary arterial hypertension. This study compared the outcomes of bilateral lung transplantation (BLT) with cardiac defect repair vs combined heart-lung transplantation (HLT). This study presents an updated analysis using a US national registry to evaluate the outcomes of patients diagnosed with ES who underwent HLT or BLT with repair of cardiac defects. This study identified patients with ES who underwent thoracic transplantation from 1987 to 2018 from the United Network for Organ Sharing database. Survival curves were estimated by using the Kaplan-Meier method and were compared by using the log-rank test. During the study period, 442 adults with ES underwent thoracic transplantation (316 HLTs and 126 BLTs). Following BLT, overall survival 1, 5, and 10 years' posttransplant was 63.1%, 38.5%, and 30.2%, respectively. Following HLT, overall survival 1, 5, and 10 years' posttransplant was 68.0%, 47.3%, and 30.5% (P = .6). When survival analysis was stratified according to type of defect, patients with an atrial septal defect had better survival following BLT than following HLT (88.3% vs 63.2% 1 year posttransplant, P < .01; 71.1% vs 49.8% 3 years' posttransplant, P < .01; and 37.4% vs 29.9% 10 years' posttransplant, P = .08). Patients with a ventricular septal defect (VSD) exhibited better survival following HLT than following BLT (78.2% vs 49.6% 1 year posttransplant, P < .01; 55.6% vs 34.3% 5 years' posttransplant, P < .01; and 35.7% vs 26.5% 10 years' posttransplant, P = .03). The most common cause of mortality in patients with VSD undergoing BLT was cardiac ventricular failure. This study suggests that the best transplant option for patients with VSD remains HLT, which prevents subsequent development of ventricular failure. BLT with cardiac defect repair should be considered as the first-line treatment option in patients with ES due to an uncorrected atrial septal defect. These patients can be considered to have isolated and reversible right ventricular failure akin to patients with advanced pulmonary arterial hypertension. Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.