Thyroxin-binding globulin (TBG) is secreted by human hepatoma cell lines and was suggested as a tumor marker of primary hepatocellular carcinoma (HCC). However, the results of several clinical studies are contradictory. Therefore, we decided to investigate whether TBG is a valuable marker for early detection and/or followup of HCC. In 30 patients with HCC we determined TBG, thyroxine (T4), trijodothyronine (T3), alpha-feto-protein, ferritin and the sonographically determined tumor size. Twenty one of these patients had liver cirrhosis. In 19 patients hepatitis B-markers could be detected, 9 of whom with positive HBs antigen. Twenty two patients with liver cirrhosis served as controls. Serum TBG in HCC and liver cirrhosis was not significantly different (21.1 +/- 6.9 vs. 18.7 +/- 5.1 micrograms/ml). T4 (p less than 0.04) and the T4/TBG ratio (p less than 0.0002) were significantly lower in HCC. T3 and ferritin were comparable in both groups. TBG correlated with T4 (r = 0.6), but not with the sonographic tumor size, alpha-fetoprotein or ferritin. In 3 patients alpha-fetoprotein and TBG could be determined 3 to 36 months prior to the primary diagnosis of HCC. In none of these patients an increase of TBG was detected before diagnosis of HCC. In the 4 patients under chemotherapy, TBG decreased after the first course. Three of these patients showed further decreasing TBG values in spite of an increasing tumor size. We conclude that in our patients TBG is no valuable tumor marker for the early diagnosis or follow up of HCC.