The purpose of this study was to investigate the use of a radiolabeled mouse monoclonal antibody (and its F(ab′)2 fragment) against α-fetoprotein in the scinti-graphic diagnosis of hepatocellular carcinoma. Twenty-six southern African Blacks and one Caucasian with hepatocellular carcinoma and four patients with other malignant tumors of the liver were studied. Although six hepatocellular carcinomas appeared to selectively concentrate α-fetoprotein antibody, one of these tumors was not producing α-fetoprotein. Moreover, in another 18 patients with α-fetoprotein-producing hepatocellular carcinomas, uptake of α-fetoprotein antibody was at best only equal to that in nontumorous hepatic tissue, and three hepatocellular carcinomas that were not producing α-fetoprotein concentrated the antibody to the same extent as did the α-fetoprotein-producing tumors and hepatic tissue. All four tumors other than hepatocellular carcinoma concentrated α-fetoprotein antibody as well as did hepatic tissue. These findings suggest that the penetration of hepatocellular carcinomas by α-fetoprotein antibody is a passive and nonselective process. This conclusion is supported by an in vitro study in which a non-α-fetoprotein-producing hepatic metastasis took up as much radiolabeled α-fetoprotein antibody as did three of four α-fetoprotein-producing hepatocellular carcinomas. A likely explanation for the failure of α-fetoprotein monoclonal antibody to be selectively concentrated by hepatocellular carcinomas is that α-fetoprotein is an export protein and is not expressed on the cell membranes of malignant hepatocytes.