Experiments were designed to study the effect of Zn on in vivo and in vitro insulin metabolism. The in vivo experiments involved pretreating mice with either Zn or Na, followed by i.p. [125I]iodoinsulin injection. Pretreatment of mice with Zn resulted in an accelerated and increased magnitude of binding of [125I]iodoinsulin to the liver compared to mice pretreated with Na. Results are submitted which support the probability that the changes in the amounts of intact and degraded insulin in circulation with time are related to the binding and degradation of insulin in the liver rather than in the kidney. In vivo i.p. injected insulin preferentially bound to the plasma membrane of the liver. Liver plasma membranes isolated from mice pretreated with Zn bound more [125I]iodoinsulin than plasma membranes of Na-pretreated mice. In vitro experiments employing isolated liver plasma membranes demonstrated that added Zn increased the binding and inhibited the degradation of insulin. Two receptors may exist, one at which degradation of [125I]iodoinsulin occurs and another at which degradation does not occur.