High-affinity agonists for the retinoic acid X receptors (RXR) have pleotropic effects when administered to humans. These include induction of hypertriglyceridemia and hypothyroidism. We determined the effect of a novel high-affinity RXR agonist with potent antihyperglycemic effects on thyroid function of female Zucker diabetic rats and nondiabetic littermates and in db/ db mice. In both nondiabetic and ZFF rats, AGN194204 causes a 70–80% decrease in thyrotropin (TSH), 3,3′,5-triiodothyronine, and thyroxine (T₄) concentrations. In the db/ db mouse, AGN194204 causes a time-dependent decrease in thyroid hormone levels with the fall in TSH that was significant after 1 day of treatment preceding the fall in T₄levels that was significant at 3 days of treatment. Treatment with AGN194204 caused an initial increase in hepatic 5′-deiodinase mRNA levels which then fell to undetectable levels by 3 days of treatment and continued to be low at 7 days of treatment. After treatment for 5 days with AGN194204, both wild-type and thyroid hormone receptor β (TRβ^−/−)-deficient mice demonstrated a nearly 50% decrease in serum TSH and T₄concentrations. The results suggest that a high-affinity RXR agonist with antihyperglycemic activity can cause central hypothyroidism independently of TRβ, the main mediator of hormone-induced TSH suppression.