Among 18 family members, representing four generations studied, a familial form of euthyroid hyperthyroxinemia was found in 6. The increased serum total thyroxine value in all hyperthyroxinemic subjects could not be explained by abnormalities in binding proteins. Five of the six patients had a goiter, and all had increased concentrations of triiodothyronine and free thyroxine without symptoms or signs of hyperthyroidism. Basal serum levels of thyroid-stimulating hormone (thyrotropin) were normal in all six; in the four who were tested, these levels responded normally to thyrotropin-releasing hormone (TRH). The normal suppression of basal and TRH-stimulated thyrotropin increase after administration of triiodothyronine did not occur. These patients seem to have resistance of peripheral and pituitary tissues to the actions of thyroid hormones. Family studies revealed that the disorder appeared as a new sporadic mutation and was consistent with an autosomal-dominant mode of inheritance. This disorder, an important example of euthyroid hyperthyroxinemia, should not be confused with Graves' disease.