Hepatopulmonary syndrome (HPS) is a triad of liver dysfunction, hypoxemia, and intrapulmonary vascular dilatation. We describe the prevalence and clinical features of HPS at a pediatric liver transplant center. Patients referred to Children's Healthcare of Atlanta/Emory University transplant program from February 1999 to May 2005 were reviewed. Oxygen saturation in room air was screened by percutaneous pulse oximetry. HPS cases were compared with similar age non-HPS recipients (n = 38) to determine differences in clinical characteristics, Pediatric End-Stage Liver Disease (PELD) scores, and posttransplantation survival. Of 211 patients referred and 114 patients transplanted, 7 met criteria for HPS (3.3% and 6.1%, respectively). Patients with HPS had lower PELD score (-0.4 +/- 5.9 vs. 11 +/- 11; P = 0.01) and total bilirubin (1.7 +/- 1.1 vs. 11.2 +/- 10.1; P = 0.02) at the time of transplantation. Four of 7 patients with HPS had polysplenia/interrupted inferior vena cava (PS/IVC) compared with 0 of 38 age-matched controls (P = 0.0002). Three patients with HPS did not have cirrhosis; 2 of these 3 had PS/IVC. All HPS cases normalized room air oxygen saturation by 6 months, and survival after transplantation in HPS cases was 100%. Marked hepatic synthetic or biochemical dysfunction may not be present, and cirrhosis is not a requirement for the development of HPS in children. HPS in children is frequently associated with PS/IVC. Histologic evidence of abnormal intrahepatic portal vein flow and the demonstration of portosystemic communications at any level should be sought in children presenting with unexplained intrapulmonary vascular dilatation. Liver transplantation for HPS in childhood may be appropriate even in the absence of cirrhosis.