We have identified centrilobular necrosis (CLN) as an unusual pathological finding in our pediatric orthotopic liver transplantation (OLT) population. The aims of this study were to describe the associated pathologic and clinical features of post-OLT CLN and determine its prognostic implications. Methods: We reviewed the post-OLT biopsy reports from pediatric recipients during 1985-1995. Biopsies with reported centrilobular (CL) changes were independently graded in a blinded fashion by two pathologists for evidence of CLN (zonal distribution, active necrosis, hepatocyte dropout, and CL fibrosis) and associated features: cellular rejection; ductopenic rejection; other findings (i.e., bile duct proliferation, cholestasis, portal fibrosis). The biopsy with the most active CLN was chosen as representative of an episode. CLN recurrence following retransplantation was counted as a new episode. Biopsy findings were correlated with clinical data and outcome. Results: 47 episodes of CLN were identified in 443 allografts. Episodes in 26 allografts (23 patients; males = 11, females = 12) were fully graded and correlated with clinical data and outcome. Fifteen episodes were associated with cellular rejection, either in the same biopsy (n=12) or within the week prior (n=3), and two with ductopenic rejection. Four were associated with vascular thrombosis. No clear etiology was identified in 5 patients; 2 also had cholangitis lenta (cholestasis and bile ductular proliferation related to intraabdominal infection). Of the remaining 3 biopsies, 2 showed only CL dropout, suggesting a resolution of some previous insult. Outcome of 23 patients with CLN: graft failure in 19 (retransplantation in 16; 3 deaths without); no graft failure in 4 (2 well (1 with portal fibrosis); 2 with chronic poorly functioning liver). Retransplant outcome: 9 deaths; 3 CLN (1 recovery, 2 ductopenic rejection); 4 no CLN (2 normal recovery, 2 ductopenic rejection). Overall patient outcome: 12 deaths; 4 ductopenic rejection; 2 chronic poorly functioning liver; 5 alive and well. Conclusions: CLN in pediatric OLT recipients is associated with cellular rejection, ductopenic rejection or acute vessel thrombosis in the majority cases, but is unexplained in a subset of patients. The observed rates of mortality (12/23) and retransplantation (16/23) in patients with CLN compare unfavorably with non-CLN patients and indicate that post-OLT CLN has negative prognostic implications.