Most patients with the syndrome resistance to thyroid hormone (RTH) express a mutant thyroid hormone receptor β (TRβ) with transdominant negative transcriptional effects. Since no patient with a mutant TRα has been identified, we introduced a point mutation into the mouse thyroid hormone receptor (TRα1) locus originally found in the TRβ gene, that reduces ligand binding 10-fold. Heterozygous 2- to 3-week- old mice exhibit a severe retardation of post-natal development and growth, but only a minor reduction in serum thyroxine levels. Homozygous mice died before 3 weeks of age. Adult heterozygotes overcome most of these defects except for cardiac function abnormalities, suggesting that other factors compensate for the receptor defect. However, the additional deletion of the TRβ gene in this mouse strain caused a 10-fold increase in serum thyroxine, restored hormonal regulation of target genes for TRs, and rescued the growth retardation. The data demonstrate a novel array of effects mediated by a dominant negative TRα1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment.