Background: Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein-losing enteropathy (PLE, P). The post-HTx effects of this altered immune phenotype are not well studied. Methods: In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post-HTx. Results: The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L−P, n = 23; −L+P, n = 10; and −L−P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L−P: 86%, −L+P: 87%, −L−P: 89%, p =.9). Freedom from first infection post-HTx was greatest among −L−P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the −L−P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L−P: 1, −L+P: 1.3, −L−P: 0.3 infections/year, p <.001) and were similar to a non-single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post-HTx, differed among the groups. Conclusions: Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post-HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients.