Steroid receptor co‐activator 1 (SRC‐1) is a transcription co‐factor that enhances the hormone‐dependent action, mediated by the thyroid hormone (TH) receptor (TR) and other nuclear receptors. In vitro studies have shown that SRC‐1 is necessary for the full expression of TH effect. SRC‐1 knockout mice (SRC‐1−/−) provide a model to examine the role of this co‐activator on TH action in vivo. At baseline, SRC‐1−/− mice display resistance to TH (RTH) as evidenced by a 2.5‐fold elevation of serum TSH levels, despite a 50% increase in serum free TH levels as compared with wild‐type (SRC‐1+/+) mice. When mice were made hypothyroid, TSH levels increased, obliterating the difference between SRC‐1+/+ and SRC‐1−/− mice observed at baseline. In contrast, the decline of TSH by treatment with l‐triiodothyronine was severely blunted in SRC‐1−/− mice. These data indicate that SRC‐1 is not required for the upregulation of TSH in TH deficiency. However, SRC‐1 enhances the sensitivity of TSH downregulation by TH. This is the first demonstration of RTH caused by a deficient co‐factor other than TR. It supports the hypothesis that a putative defect in the SRC‐1 gene or another co‐factor could be the cause of RTH in humans without mutations in the TR genes.