Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TRα and TRβ. Little is known about effects of ligands that preferentially interact with the two different TR subtypes. In the current study the comparison of the effects of the novel synthetic TRβ-selective compound GC-1 with T₃ at equimolar doses in hypothyroid mice revealed that GC-1 had better triglyceride-lowering and similar cholesterol-lowering effects than T₃. T₃, but not GC-1, increased heart rate and elevated messenger RNA levels coding for the I_f channel (HCN2), a cardiac pacemaker that was decreased in hypothyroid mice. T₃ had a larger positive inotropic effect than GC-1. T₃, but not GC-1, normalized heart and body weights and messenger RNAs of myosin heavy chain α and β and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRβ-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate. The preferred accumulation of GC-1 in the liver vs. the heart probably also contributes to its marked lipid-lowering effect vs. the absent effect on heart rate. These data indicate that GC-1 could represent a prototype for new drugs for the treatment of high lipid levels or obesity.