Childhood cancer survivors transfused before 1992 are at risk for chronic hepatitis C (HCV), infection. In 1995, St Jude Children's Research Hospital initiated an epidemiologic study of childhood cancer survivors with transfusion-acquired HCV. Of the 148 survivors with HCV confirmed by second-generation enzyme immunoassay, 122 consented to participate in the study. Their current median age is 29 years (range, 9 to 47 years). At enrollment, polymerase chain reaction (PCR) testing indicated chronic infection in 81:1%; genotype 1 was the most common viral genotype. Liver biopsy in 60 patients at a median of 12.4 years from the diagnosis of malignancy showed mild (28.8%) or moderate (35.6%) fibrosis; 13.6% had cirrhosis. Elevated body mass index was associated with histologic findings of increased steatosis (P = .008). Antimetabolite chemotherapy exposure was associated with early progression of fibrosis. Significant quality-of-life deficits were observed in noncirrhotic adult survivors. Antiviral therapy resulted in clearance of infection in 17 (44%) of 38 patients to date. Six patients have died; 1 patient with decompensated cirrhosis died of variceal bleeding. Despite a young age at HCV infection, the progression of liver disease in childhood cancer survivors is comparable to that seen in adults.