We have studied the structure and function of the partially purified insulin receptors from liver and skeletal muscle in a rat model of severe chronic uremia. 125I-insulin binding was higher in the liver from uremic rats when compared with ad libitum- and pair-fed controls. Furthermore, the ability of insulin to stimulate the autophosphorylation of the beta-subunit and insulin receptor kinase activity using Glu80, Tyr20 as exogenous phosphoacceptor was increased in the liver of the uremic animals. The structural characteristic of the receptors, as determined by electrophoretic mobilities of affinity labeled alpha-subunit and the phosphorylated beta-subunit, were normal in uremia. 125I-insulin binding and insulin receptor kinase activity were similar in the skeletal muscle from uremic and pair- and ad libitum-fed animals. Thus our data are supportive of the hypothesis that in liver and muscle of chronic uremic rats, insulin resistance is due to a defect(s) distal to the insulin receptor kinase.