Many centers perform biopsies on transplanted livers annually to assess allograft function because serum biochemical tests do not always correlate with histological findings. Although criteria exist for diagnosing acute cellular rejection, no similar criteria exist to describe the histopathological changes observed in the "normal" liver of an immunosuppressed but healthy child. The purpose of this study was to define the histopathological changes in the allografted livers of healthy children who have undergone transplantation and to evaluate them during long-term follow-up. One hundred fifty-eight yearly protocol liver biopsy specimens of 54 children who received transplants between January 1988 and March 1996 and at least 1 year of follow-up were reviewed, and the biopsy findings were correlated with those of serum tests of liver function performed concomitantly. Thirty-three biopsy specimens were excluded because serum transaminase levels were abnormal, the biopsy specimen was abnormal and diagnostic for a specific lesion, or follow-up showed progression of a specific disease process. In addition, time zero biopsy specimens from 21 of the 54 children were available for comparison. In the protocol biopsy specimens, portal and/or parenchymal mononuclear inflammatory infiltrates were frequent findings (48% and 25%, respectively). Other less common features were mild fibrosis (8%) and focal pericholangitis (6%). Findings in both protocol and time zero biopsy specimens included minimal to mild bile ductular proliferation (15% and 9.5%, respectively) and rare hepatocyte necrosis (1.6% and 5%). No yearly protocol biopsy specimens resulted in any patient benefit. Transplanted livers in immunosuppressed children who are clinically healthy and have normal transaminase levels commonly show histological changes consisting of scattered, mild to moderate, portal and/or parenchymal mononuclear infiltrates that are clinically insignificant. Yearly protocol biopsies in healthy pediatric recipients have been abandoned by the investigators after 3 years of follow-up.