INTRODUCTION: The number of heart transplants in adults with congenital heart disease (CHD) is increasing, though outcomes remain unfavorable compared to those without CHD. The etiology of this mortality difference remains uncertain. Panel reactive antibody (PRA) is a predictor of survival post-transplantation, and adult CHD patients have been observed to have higher PRA levels. Here we assessed the relationship between PRA and outcomes in adult patients with CHD who underwent heart transplantation. METHODS: This is a retrospective cohort study using the 2004-2015 ISHLT Thoracic Organ Transplant Registry to investigate the role of sensitization in the observed excess mortality. The composite outcome of mortality or graft failure within 1-year of transplantation was compared among CHD vs. non-CHD recipients, according to sensitization as measured by pre-transplant panel reactive antibodies (PRA). RESULTS: Adults with CHD (n = 1188) had higher PRA level compared to non-CHD (n = 38,201) recipients (27% vs. 18% PRA>10%, respectively, p < 0.001). CHD diagnosis remained independently associated with a higher incidence of the composite outcome in multivariable analysis after adjusting for PRA and other variables. Further, even after age-matching, patients with CHD and PRA ≤10% were at higher risk of the primary outcome compared to non-CHD (OR 2.1 [1.4-3.4], p = 0.001), though both groups had comparable outcomes when PRA was >10% (OR 1.1 [0.6-2.0], p = 0.852). CONCLUSIONS: Adults with CHD are more likely to have higher sensitization and worse outcomes than non-CHD recipients. Higher sensitization rates alone do not fully explain their excess risk of adverse outcomes after heart transplantation.