Human leukocyte antigen (HLA) sensitization of pediatric heart recipients increases their risk of rejection and graft loss. As more children are placed on mechanical circulatory support (MCS) as a bridge to transplant, the risk factors for development of sensitization warrant further study. A single-center retrospective review of 36 children who received MCS identified 22 patients supported with either extracorporeal membrane oxygenation (ECMO) (n = 15) or ECMO-ventricular assist device (VAD) (n = 7) with paired (pre-MCS/post-MCS) panel reactive antibodies (PRA) or only negative post-MCS PRAs. Four patients (18%) became sensitized post-MCS (one ECMO-only patient, three ECMO-VAD patients). No difference was found between sensitized and nonsensitized patients in terms of congenital heart disease versus primary cardiomyopathy (p = 0.096), duration of MCS (38 days vs. 14 days, p = 0.233), or volume of blood product transfusions (358.6 ml/kg vs. 612.7 ml/kg, p = not significant). By multivariable analysis, the association of sensitization with older age at MCS (p = 0.076) and history of homograft (p = 0.064) approached significance. Pediatric patients supported with MCS are at low risk of developing HLA sensitization. Diagnosis, MCS duration, and volume of transfused blood products do not appear to be associated with HLA sensitization, but there is a suggestion of an association with older age at MCS and history of a homograft.