Background: FK506(FK) based immunosuppression after pediatric heart transplantation has replaced cyclosporine A(CSA) therapy at many institutions. The purpose of this study was to evaluate rejection outcome, left ventricular (LV) function and side effects associated with these two immunosuppressive regimens. Methods: We reviewed the records of 35 pts age 3 days to 19yrs (median 9yrs) who underwent 37 heart transplants (HT) between 1990-1996. Recipient diagnosis included idiopathic congenital or acquired cardiomyopathy (59%), structural congenital heart disease (35%), and retransplant for acute rejection (5%). All pts received induction immunosuppression with solumedrol and 35/37 received OKT3. The first 26 HTs were treated with CSA, azathioprine(AZA) and daily prednisone and the last 11 HTs were treated with FK and prednisone tapered off over 4-6 months. Endomyocardial biopsies, M-mode echocardiograms and clinical data were compared. Results: Groups were similar for age (CSA 8.3±5.1 vs FK 7.7±4.7y). Mean follow-up was longer for CSA pts(33.8±12.2months -CSA and 15.9±8.4 months -FK). Eight (31%) CSA deaths occurred; acute rejection (5), sepsis (1), posttransplant lymphoproliferative disease (PTLD) (1), and liver failure (1). There were 3(27%) FK deaths; rejection (1), sepsis (1), and neurologic injury (1). International Society for Heart and Lung Transplantation ≥grade 3 rejection requiring short course solumerol therapy was present in 31/604 (5%) of CSA and 4/106 (4%) of FK biopsies. Rejection episodes per pt were 1.2±0.5(CSA) and 0.5±0.2 (FK). CSA side effects included: hirsutism (27), hypertension (25), hospitalized infection episodes (16), gingival hyperplasia requiring dental surgery (4) and PTLD (1). FK side effects included: hospitalized infection episodes (2), transient IDDM (2), PTLD (2) and transient nephrotoxicity (2). Mean fractional shortening values were not statistically significant between groups 6 months and one year post transplant. Conclusion: Early outcome after heart transplant demonstrated no significant difference between pts treated with CSA, AZA, and daily prednisone and those treated with FK and 4-6 months of prednisone with respect to mortality, episodes of severe rejection and LV function. Morbidity is similar between groups with hypertension, hirsutism, episodes of infection and gingival hyperplasia significantly increased in CSA treated pts.