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To assess the differences in rejection and infection complications between the most common contemporary immunosuppression regimen in pediatric heart transplantation (cytolytic induction, tacrolimus based) and classic triple-therapy (cyclosporine based without induction).We performed a retrospective, historical-control, observational study comparing outcomes in patients who underwent traditional immunosuppression (control group, n = 64) with those for whom the contemporary protocol was used (n = 39). Episodes of rejection, viremia (cytomegalovirus or Epstein-Barr virus), serious bacterial or fungal infections, anemia or neutropenia requiring treatment in the first year after heart transplantation, and 1-year survival were compared between traditional and contemporary immunosuppression groups.The 2 groups were similar with respect to baseline demographics. There were no differences in risk of cytomegalovirus, Epstein-Barr virus, or bacterial or fungal infections in the first year post-transplantation. Patients in the contemporary group were more likely to need therapy for anemia (51% vs 14%, P < .001) or neutropenia (10% vs 0%, P = .019). However, more contemporary protocol patients were rejection-free in the first year post-transplantation (63% vs 41%, P = .03). Overall graft survival was similar between groups (P = .15).A contemporary immunosuppression regimen using tacrolimus, mycophenolate mofetil, and induction was associated with less rejection in the first year, with no difference in the risk of infection but greater risk of anemia and neutropenia requiring treatment. Long-term follow-up on these patients will evaluate the impact of the immunosuppression regimen on survival.