The response in serum thyrotropin (TSH) to synthetic thyrotropin-releasing hormone (TRH) as well as serum free thyroxine index (FT₄I) and free triiodothyronine index (FT₃I) was investigated in six patients with familial thyroxine-binding-globulin (TBG) deficiency. The total serum thyroxine (T₄) and triiodothyronine (T₃) concentrations were significantly decreased, compared with those of normal subjects (3.4±0.9 μg/dl, mean±S. D. vs. 9.0±1.5 μg/dl, p<0.01 and 87±27 ng/dl vs. 153±37 ng/dl, p<0.01, respectively). FT₄I was lower than the normal range in all but one (5.3±1.5 vs. 8.9±1.6, p<0.01), whereas FT₃I was all in the normal range and of no significant difference from the normal control (132±22 vs. 148±25). Serum TSH concentrations in TBG deficiency were all in the normal range (1.0-4.2 μU/m/) and the maximum TSH increments following TRH 500 μg iv were 8.9±2.0 μU/ml and of no significant difference from the normal control (10.2±4.5 μU/ml). These results indicate that the euthyroid state in familial TBG deficiency is more clearly defined by TRH-test and the normal response to TRH in familial TBG deficiency is presumably under the control of the serum free T₃ level rather than the serum free T₄ level.