Endomyocardial biopsy remains the 'gold standard' for the diagnosis of acute rejection after cardiac transplantation, but few guidelines exist to determine the indications for its use in pediatric cardiac transplant recipients. To determine the usefulness of surveillance endomyocardial biopsy, 176 biopsies were reviewed from 12 patients, aged 0.5-16 (average 9.7) yr, maintained on cyclosporine, azathioprine and prednisone immunosuppression, and followed 2.8-45.5 (average 26.3) months after cardiac transplantation. Children old enough to cooperate (n = 6) underwent biopsy on nine occasions in the first 6 months after transplantation and quarterly thereafter. Children too young to cooperate (n = 6) underwent biopsy with general anesthesia on four occasions in the first 6 months after transplantation and every 6 months thereafter. Additional biopsies were performed as warranted by symptoms or noninvasive tests. A new episode of acute rejection was present in 13 biopsies (7%); continuing or resolving rejection in 19 others (11%). Remaining biopsies had no evidence of rejection (82 biopsies, 47%), had lymphocytic infiltrates insufficient for diagnosis (47 biopsies, 27%), were inadequate for diagnosis (14 biopsies, 8%), or were consistent with ischemia (1 biopsy, 0.5%). During the first 6 postoperative months, eight of 101 biopsies were positive for rejection, three occurring on routine surveillance biopsy. After 6 months, five of 75 biopsies showed a new episode of rejection, only one occurring on routine surveillance biopsy. Based on this data, it is concluded that: 1) episodes of rejection are relatively uncommon with triple drug immunosuppression; 2) surveillance biopsies in the first 6 months after cardiac transplantation may show unsuspected rejection; and 3) routine surveillance biopsies more than 6 months after cardiac transplantation are unlikely to show rejection in the absence of symptoms or other tests.