To determine the prevalence of elevated serum concentrations of thyroxine binding globulin (TBG) in patients with hepatocellular carcinoma (HCC) and the influence of the associated cirrhosis, TBG was measured in 39 patients with HCC, 22 with and 17 without cirrhosis, in 20 patients with cryptogenic macronodular cirrhosis but without HCC, and in 40 matched controls. The mean serum TBG concentration in the patients was 34.5 ± 17.7 μg per ml, compared to 21.4 ± 6.8 μg per ml in controls and 20.5 ± 6.3 μg per ml in cirrhosis without HCC (p < 0.01). The presence or absence of cirrhosis in the HCC patients did not significantly influence the frequency with which elevated TBG levels were found; levels were normal in every subject with cirrhosis and no HCC. The mean thyroxine (T4): TBG ratio was 5.58 ± 1.78 in controls and was reduced in HCC patients with both elevated (3.33 ± 0.80, p < 0.001) and normal TBG values (4.39 ± 1.90, p < 0.05), and in cirrhotics without HCC (4.29 ± 1.01, p < 0.01). T4 and TBG concentrations correlated significantly in controls, in HCC patients with elevated TBG, and in the cirrhotics without HCC. It is concluded that in patients with HCC (i) TBG levels may be elevated both in the presence or absence of cirrhosis; (ii) there is reduced binding of T4 TBG, and (iii) a low T4:TBG ratio excludes the diagnosis of hyperthyroidism in the presence of high T4 levels. TBG levels are normal in patients with cryptogenic macronodular cirrhosis without HCC.