BACKGROUND Endomyocardial biopsy remains the primary means of rejection surveillance after orthotopic heart transplantation in adults. Perpetual surveillance endomyocardial biopsy has been questioned, however, because of low yield beyond the early posttransplantation period. This issue has not been adequately studied in the pediatric population. The objectives of this study were to define the rate of rejection in infants undergoing orthotopic heart transplantation, correlate rejection with signs and symptoms, and evaluate the utility of surveillance endomyocardial biopsy. METHODS Records of all patients 24 months of age or younger undergoing orthotopic heart transplantation were reviewed; 38 patients underwent 42 transplantation; 256 endomyocardial biopsies were performed for surveillance, cardiac symptoms, noncardiac symptoms, or lowered immunosuppression. RESULTS There were 22 rejection episodes International Society for Heart and Lung transplantation grade 1B or higher, half of which occurred in neonates 30 days of age or younger. Linearized rejection rates and actuarial freedom from rejection were not different between neonates and older infants. Linearized rejection rates reached a plateau 3 months after orthotopic heart transplantation of 0.07 episodes/100 patient days. No positive surveillance endomyocardial biopsies were obtained beyond 6 months after orthotopic heart transplantation. The probability of a positive biopsy (International Society for Heart and Lung Transplantation grade 1B or higher) was 20% or more for any other indication (odds ratios for rejection were 12.9 for cardiac symptoms, 3.3 for noncardiac symptoms, and 10.8 for lowered immunosuppression as determined by logistic regression more than 6 months after orthotopic heart transplantation). CONCLUSIONS Rejection rates are not different between neonatal and older infants, and endomyocardial biopsies done solely for surveillance beyond 6 months after orthotopic heart transplantation rarely yield positive results.