A large percentage of patients with advanced-stage hepatocellular carcinoma (HCC) have a recurrence of tumor in the liver or lung after primary resection and even after orthotopic liver transplantation. One reason for this may be the presence of small numbers of tumor cells circulating in the blood before surgery or the liberation of tumor cells into circulation during surgical manipulation. We tested this hypothesis by measuring messenger RNA (mRNA) for human albumin gene as a liver cell marker with the highly sensitive reverse transcriptase polymerase chain reaction (RT-PCR) technique. Albumin mRNA was not found in peripheral blood from normal humans (0 of 6), from patients with liver cirrhosis (0 of 10), from other tumors metastatic to liver (0 of 10), or during liver transplant surgery for cirrhosis (0 of 10). In patients with advanced-stage HCC (TNM stages III and IV), albumin mRNA was detected (16 of 17) in peripheral blood. After liver transplantation in the HCC patients, the level of mRNA decreased below the detectable limit (0 of 9). Three of these patients again had detectable mRNA levels when they had recurrence of HCC after liver transplantation. Patients with stage I HCC did not have detectable expression. These results suggest that circulating tumor cells are present in patients with advanced-stage HCC, which may be one of the reasons why these patients have a high incidence of tumor recurrence after apparently definitive surgical resection and even after liver transplantation.