Evaluation of a family in which males were clinically euthyroid despite having low serum total T4 (TT4) and free T4 index (FT4I) values revealed the presence of a new inherited T4-binding globulin (TBG) variant (TBG-San Diego). Two brothers had low TT4 (39 and 49 nmol/L; normal range, 64-154 nmol/L) and FT4I (4.0 and 4.4; normal range, 6.0-10.5) values, while their grandfather, despite treatment with T4, had a low TT4 (53 nmol/L) and normal FT4I (7.2) in the presence of suppressed TSH (less than 0.1 mU/L). When measured by RIA, the mean TBG concentration (TBG-RIA) of the three affected males was low normal [160 +/- 56 (+/- SD) nmol/L; normal range, 151-253]. Their TBG-binding capacity measured by a T4 binding assay at saturation (TBG-CAP) was similar, giving a mean TBG-RIA/TBG-CAP ratio not significantly different from 1.0. In these males, the TBG affinity for T4 (Ka = 0.48 +/- 0.04 x 10(10) mol-1) was less than that in subjects with the common type TBG (TBG-C; Ka = 1.10 +/- 0.14 x 10(10) mol-1; P less than 0.0001) and similar to that in Aboriginal males from Australia with the variant TBG-A (0.52 +/- 0.10 x 10(10) mol-1). TBG affinity for T3 in the affected males (Ka = 0.68 +/- 0.05 x 10(9) mol-1) was less than that in subjects with TBG-C (1.39 +/- 0.12 x 10(9) mol-1; P less than 0.00001), but greater than that in males with TBG-A (0.44 +/- 0.03 x 10(9) mol-1; P less than 0.0005). The rate of TBG denaturation at 56 C was increased in the affected males (t1/2 = 28.4 and 26.9 min) compared to that in subjects with TBG-C (t1/2 = 54.1 +/- 7.1 min), but was lower than that in males with TBG-A (t1/2 = 20.8 +/- 1.9). A value intermediate between those in affected males and normal subjects was found in serum from an obligatory heterozygote. Microheterogeneity on isoelectric focusing was normal. The exact nature of this structural TBG variant is not yet known. The presence of a TBG mutant should be considered in healthy, clinically euthyroid patients with low serum TT4 and free T4 index values, especially when such low values are found in several members of the same family.