We have previously shown that in the insulin-resistant obese hyperglycemic mouse (ob/ob) there is a deficiency in the number of insulin receptor sites on hepatocytes, adipocytes, and thymic lymphocytes. We now find that concentration of insulin receptors on liver plasma membranes is decreased in the db/db mouse, another form of inherited obesity, and in normal mice that became obese after treatment with gold thioglucose, while thin mice, heterozygous for the ob mutation (ob/+), have normal insulin binding. With acute and chronic food restriction of the ob/ob and gold thioglucose obese mice, there is reduction in hyperinsulinemia and an associated increase in the insulin receptor concentration toward normal. In contrast, when fasting ob/ob mice were given exogenous insulin to maintain the hyperinsulinemia, insulin receptors failed to increase. Thus, in all cases, there was a consistent relationship between the degree of hyperinsulinemia and of insulin receptor loss. These findings suggest that decreased insulin binding is a characteristic feature of the insulin resistance of obesity, and that sustained hyperinsulinemia is a major factor in the control of the concentration of insulin receptors on target cells.