Several cardiac genes possess thyroid hormone (TH) response elements regulated by TH receptors. Mutation in TR- gen cause the human syndrome of resistance to thyroid hormones (RTH), which is characterized by elevated serum concentration of T₄ and T₃ and variable degrees of insensitivity to TH. It is unclear, however, whether a mutant TR- could function as a dominant negative in the heart when expressed from the endogenous locus. A well-described RTH (337T) was either introduced into germline of mice (KI-mut) or expressed as a transgene in the heart using a cardiac specific promoter (KS-mut). Mice were studied at baseline, after PTU (PTU) or after PTU and T₃ treatment (PTU+T₃). PTU+T₃ treatment significantly increased left ventricular (LV) mass in all groups compared with baseline measurements, although the increase in LV mass was significantly less in KI-mut animals. Baseline heart rates (HR) were similar in wild-type (WT) and KI-mut but were lower in KS-mut animals. After TH deprivation (PTU), HR decreased in WT and KI-mut animals; similarly HR increased in WT and KI-mut after PTU+T3. In contrast, HR in KS-mut animals did not change after either treatment. Except for cardiac hypertrophy, the presence of a germline TR- mutation had surprisingly little effect on cardiac function.