A 51-year-old heart transplant recipient who developed subfulminant hepatic failure because of organ-transmitted hepatitis C virus (HCV) infection is described. He presented with a predominantly cholestatic liver damage after heart transplantation. An extensive evaluation, including abdominal ultrasound and computed tomography scan and endoscopic retrograde cholangiopancreatography was unrevealing. Liver biopsy, however, was suggestive of a large duct obstruction with prominent portal and pericellular fibrosis, marked cholestasis, pericholangitis with marked ductular proliferation, and diffuse hepatocyte degeneration. Antibody to HCV (anti-HCV) was initially negative. He deteriorated in the ensuing 3 months. A repeat enzyme immunoassay-2 test for anti-HCV 4 months after initial presentation was weakly positive. Quantitation of serum HCV RNA by branched DNA assay revealed high level viremia, 547 x 10(6) genome equivalents per milliliter. Using in situ polymerase chain reaction, HCV RNA was detected in the cytoplasm in > 80% of the hepatocytes. The patient underwent interferon alfa therapy, and serum HCV RNA levels were reduced 20-fold after four doses. Unfortunately, the patient developed pulmonary aspergillosis and died. This case illustrates that in immunosuppressed patients anti-HCV is not a good marker for the diagnosis of HCV infection, and HCV can cause a progressive form of cholestatic liver disease mimicking a large duct obstruction.