The syndrome of resistance to thyroid hormone (RTH) is charac- terized by decreased tissue responsiveness to thyroid hormones. In- heritance is usually autosomal dominant due to mutations in the ligand-binding domain or adjacent hinge region of the thyroid hor- mone receptor b (TRb) gene. Six of 65 families with the RTH pheno- type studied in our laboratory had normal TRb1 and TRb2 gene sequences. Their clinical characteristics were not different from those of subjects with TRb gene mutations. Four of the 6 families were amenable to linkage analysis, and TRa involvement was excluded. Candidate genes were then evaluated for their possible involvement in the RTH phenotype in these 4 families: 2 coactivators (NCoA-1 (SRC-1) and NCoA-3 (AIB-1)), 2 corepressors (NCoR and SMRT), and a coregulator (RXRg). DNA was obtained from 8 affected subjects and 41 of 45 living first degree relatives. In 2 of the 4 families, the mode of inheritance could be determined by pedigree analysis and was found to be autosomal dominant. Linkage analyses were performed using polymorphic markers near or within the 5 candidate genes. When analyses were not informative or linkage could not be excluded, direct sequencing of the genes in question was performed. Involvement of NCoA-1 was excluded in all four families assuming autosomal dominant inheritance. Roles for NCoR, SMRT, and NCoA-3 were excluded in three and a role for RXRg was excluded in two of the four families. However, if the two families without proven dominant mode of inheritance were compound heterozygous, only the involvement of NCoA-1 could be excluded in both. Roles for NCoR, SMRT, and RXRg were excluded in one of these two families. Thus, NCoA-1 and RXRg genes were not found to be the cause of RTH in subjects without TR gene mutations even though the absence of NCoA-1 and RXRg is the cause of RTH in mice. Involvement of other candidate genes in the mediation of thyroid hormone action as well as intracellular hormone transport needs to be explored in these families with non-TRb ,T R a RTH. (J Clin Endocrinol Metab 85: 3609 -3617, 2000)