We here report three kindreds with a total of 19 persons affected with central and peripheral resistance to thyroid hormones: one kindred with 10 affected persons is the largest reported to date. Male to male transmission of the syndrome was evident in two kindreds, consistent with an autosomal dominant mode of inheritance. During several years of follow up, the degree of resistance to thyroid hormones did not ameliorate. Within a given kindred, a given tissue or tissues was consistently more resistant to thyroid hormone than other tissues. The pattern of tissues most affected in one kindred differed from that of another kindred, perhaps reflecting the inherited underlying molecular defects. Members of kindred A frequently had bone involvement, and several had learning disabilities and recurring infections, while most members of kindreds B and C had little bone involvement, but marked hepatic and cardiac resistance to thyroid hormones. Kinetic studies of the binding of [125I] triiodo-L-thyronine to nuclei from skin fibroblasts from affected patients from each of the kindreds demonstrated decreased maximum binding as compared to normal fibroblasts, but there was no correlation between this parameter and other features of the disease. Four of the 19 patients had previously been treated inappropriately with antithyroid therapies, demonstrating how the syndrome may be readily confused with Graves' disease by some clinicians. Behavior or school performance improved in all children treated with thyroid hormones, and a growth spurt was documented in six children, but objective improvement in IQ scores was not demonstrated, suggesting that initiation of hormone therapy at an early age may be important for maximum benefit.