Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8 deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T₃ content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T₃ content is high, resulting in increased D1, suggesting that in this tissue TH entry is Mct8-independent. We tested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given 3 different doses of DITPA. Effects were compared to treatment with two doses of L-T₄. As expected, physiological doses of L-T₄ normalized serum TSH, brain D2 and liver D1 in Wt mice but not in the Mct8KOs. The higher dose of T₄ suppressed TSH in the Wt mice, normalized TSH and brain D2 in Mct8KO mice but produced a thyrotoxic effect on liver D1 in both genotypes. In contrast DITPA produced similar effects on TSH, D2 and D1 in both Wt and Mct8KO mice. The higher dose fully normalized all measurements and other parameters of TH action. Thus, DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver. The potential clinical utility of this analogue to patients with MCT8 mutations requires further studies.