Antibodies to insulin receptors purified from rat liver membranes do not complete with [125I]insulin for binding to the insulin receptor but do precipitate solubilized receptors labeled with [125I]insulin. These antibodies have the insulin-like activities of enhancing glucose oxidation and inhibiting epinephrine-induced lipolysis in rat adipocytes. Thus, antibody binds to the receptor at a different site from that to which insulin binds, yet the interaction can initiate an effective biological response. These results indicate that the previously studied insulin-binding sites are the physiological macromolecular receptors for insulin.