Low serum total T4 associated with subnormal concentrations of thyroxine binding globulin (TBG) has been reported in up to 40% of euthyroid Australian aborigines. It has been suggested that these subjects show both diminished concentration of TBG and reduced TBG affinity for T4 (Sarne et al., 1985). We have compared 12 euthyroid aborigines with low T4 (total T4 44 +/- 5 nmol/l) and aborigines with normal T4 (T4 99 +/- 9 nmol/l, n = 12) using measurements of free T4 and T3 by equilibrium dialysis. TBG was measured both by RIA (Henning, Berlin, FRG) and a method dependent on T4 binding (Corning Immophase). Aborigines with low T4 showed lower levels of free T4 (12.6 +/- 0.6 cf. 18.7 +/- 1.0 pM), free T4 index (66 +/- 8 cf. 98 +/- 13), total T3 (1.1 +/- 0.2 cf. 1.6 +/- 0.3 nmol/l), TBG RIA (14.0 +/- 0.6 cf. 25.0 +/- 1.2 ng/l), and TBG Immophase (9.0 +/- 0.5 cf. 22.0 +/- 1.2 mg/l) (P less than 0.01), but free T3 (5.3 +/- 0.4 cf. 4.7 +/- 0.4 pM) and TSH (1.9 +/- 0.2 cf. 1.8 +/- 0.2 mU/l) were not significantly different from the values found in aborigines with normal T4. Scatchard analysis of T4 and T3 binding was performed using serum diluted 1 : 20,000 for T4 and 1 : 500 for T3 (barbitone buffer pH 8.6, 4 degrees C, dextran-coated charcoal separation). In euthyroid low T4 aborigines compared to those with normal T4, both T4 capacity (106 +/- 14 cf. 238 +/- 13 nM, P less than 0.01) and affinity (5.05 X 10(10) cf. 8.47 X 10(10) M-1, P less than 0.05) were significantly reduced. Similarly, both T3 capacity (62 +/- 10 cf. 154 +/- 16 nM, P less than 0.01) and affinity (1.67 X 10(9) cf. 2.28 X 10(9) M-1, P less than 0.02) were reduced. A substantial minority of euthyroid Australian aborigines have a TBG variant characterized by both reduced capacity and affinity of T4 and T3. These findings suggest that TBG may be both qualitatively and quantitatively abnormal in these subjects.