Background Children undergoing heart transplantation who have preformed anti-human leucocyte antigen (HLA) panel reactive antibodies (PRA) or positive retrospective crossmatch (XM) may be at increased risk for rejection and graft failure. We assessed outcomes of transplant recipients with either positive PRA before transplant or positive retrospective XM. Methods A review of 148 heart transplant patients between 1990 and 2006 was undertaken, identifying transplants in patients with pre-transplant PRA > 1% and/or a positive XM. Demographic information and detailed post-transplant outcomes including episodes of rejection, infection, and graft failure were recorded. Results There were 11 PRA positive (PRA+) transplants, 135 PRA negative (PRA−) transplants, and no PRA data on 2. There were 14 XM+ transplants, 115 XM− transplants, and no XM data on 19. Kaplan-Meier graft survival was better in XM− than XM+ patients (p < 0.015), but not different between PRA+ and PRA− Groups. Timing of first rejection and number of rejection episodes were not different between XM+ and XM− Groups or between PRA+ and PRA− Groups. Infections were not different between PRA or XM Groups. Four patients were PRA+/XM− (all PRA, 1%–10%), 7 were PRA−/XM+, and 7 were PRA+/XM+ (6 of 7 PRA >10%). Conclusions Pediatric heart transplant patients whose retrospective XM is positive are at significantly increased risk for graft failure. Elevated pre-transplant PRA may not predict increased risk of graft failure, although markedly positive PRA (>10%) predicts a positive retrospective XM. Improved treatment for pediatric transplant patients with a positive retrospective XM is needed.