The results of preliminary reports of childhood cancer survivors with hepatitis C infection (HCV) show that in none of these patients did the disease progress to liver failure or hepatocellular carcinoma (HCC). The authors describe two patients who were diagnosed with HCC more than 20 years after the treatment of childhood acute lymphocytic leukemia. Serologic testing, done at the time HCC was diagnosed, found HCV-directed antibodies, suggesting that chronic HCV infection contributed to the development of the subsequent neoplasm. Identification of infected patients will permit intervention to reduce the risk of progressive liver disease and will also assist in defining the risk of and variables contributing to progressive liver disease.