Awareness of early spread of hepatocellular carcinoma is crucial in selecting patients for surgical intervention. Alpha-fetoprotein is widely used as a serum marker for hepatocellular carcinoma. Our aim was to evaluate the specificity of alpha-fetoprotein-mRNA transcription in cells in the peripheral blood for diagnosing early spread of hepatocellular carcinoma in black Africans. Alpha-fetoprotein-, albumin- and prothrombin-mRNA were detected in peripheral blood mononuclear cells by reverse transcription-polymerase chain reaction. Alpha-fetoprotein-mRNA was shown in peripheral blood mononuclear cells in 53% (35/66) of patients with hepatocellular carcinoma, but also in 45% (10/22) of healthy blacks, 64% (14/22) of black patients with acute hepatitis, 55% (11/20) of those with chronic hepatitis or cirrhosis and 75% (9/12) of those with hepatic metastases (from a number of primary sites). Specificity of albumin- and prothrombin-mRNA was better than that of alpha-fetoprotein-mRNA, although the sensitivity was reduced. The corresponding prevalence of albumin-mRNA for each group of patients or controls was 30% (20/66), 9% (2/22), 41% (9/22), 10% (2/20), and 17% (2/12), respectively, and for prothrombin-mRNA 27% (18/66), 4.5% (1/22), 27% (6/22), 20% (4/20) and 17% (2/12), respectively. We conclude that the non-specificity of alpha-fetoprotein-mRNA transcription in peripheral blood in recognizing malignant hepatocytes in the circulation severely limits its usefulness in diagnosing the early spread of hepatocellular carcinoma in black Africans.