The assessment of new and more sensitive serum markers for hepatocellular carcinoma (HCC) represents a useful contribution to the diagnosis of small liver tumors, still amenable by surgery. We evaluated the efficacy of the tumor markers proposed during recent years for the study of HCC: alpha fetoprotein (AFP), carcinoembryonic antigen (CEA), serum ferritin (SF), tissue polypeptide antigen (TPA), and, finally, the more recently proposed des-gamma-carboxy prothrombin (DCP). Of the 227 patients included in this retrospective study, 111 had HCC, and 85 of these were also cirrhotic. The remaining 116 patients, considered as the control group, included 23 patients with liver metastases from colorectal cancer, 26 with benign hepatic lesions, 20 with tumors other than HCC without hepatic metastases, and 47 with other liver diseases. For each single tumor marker, the sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and Younden index were assessed. AFP and DCP proved to be the most effective, with sensitivity, specificity, and diagnostic accuracy of 54.9%, 97.4%, and 76.6% and of 53.3%, 88.1%, and 71.1%, respectively. The same parameters evaluated for combined use of the two markers were 74.2%, 87.2%, and 80.9%, respectively. Analysis of the other markers produced no further significant contribution. Of the 111 patients with HCC, 35 (33.3%) were positive for both AFP and DCP, 43 (41%) were positive for one of them, and 27 (25.7%) were completely negative. In the 44 patients who underwent liver resection or transplantation, DCP correlated significantly with the histological presence of microvascular thrombosis, the major factor determining long-term survival after curative surgery. As a tumor marker for HCC, DCP is at least as effective as AFP; the combined use of AFP and DCP significantly improves the chances of identifying HCC by serodiagnosis Copyright © 1995 by the American Association for the Study of Liver Diseases.