Extrathyroidal tissues of man and the rat contain a potent inhibitor of the binding of thyroid hormones to serum proteins and to an anion-exchange resin. The inhibitor is heat-labile and nondialyzable. It acts by reducing the binding affinity of thyroid hormones to serum proteins, not by reducing the number of binding sites. The tissue inhibitor is similar in several characteristics to an inhibitor described previously in the serum of some critically ill patients, suggesting that the tissue inhibitor may leak into the circulation in severe illnesses.