We report on a 41-year-old man undergoing liver transplantation for chronic hepatitis C who presented 26 months later with hepatocellular carcinoma. No evidence of hepatocellular carcinoma could be found in the native liver, although features of small cell dysplasia were prominent. Although he had recurrent hepatitis C, the transplanted liver was not cirrhotic. Chromosomal analysis was used to resolve whether this was a de novo tumor or a recurrence of an unsuspected tumor present at the time of transplantation. This male patient had received a liver from a female donor, and in situ hybridization for the Y chromosome showed reactivity in the tumor but not in surrounding nontumorous liver. Thus, this is an example of the use of chromosomal analysis to resolve the origin of a tumor occurring in the transplant setting.