We have studied insulin binding to circulating mononuclear cells obtained from 31 untreated, adult, nonobese, nonketotic diabetic subjects with fasting hyperglycemia, 40 normal subjects and four patients with fasting hyperglycemia secondary to chronic pancreatitis. Our results show that the mononuclear cells of untreated adult diabetic patients have a decreased ability to bind insulin when they are compared to cells obtained from normal subjects. The binding affinity for insulin was the same for both groups of cells, and the decreased binding could be accounted for by a 45 per cent decrease in the number of available insulin receptor sites per cell. Treatment with chlorpropamide (one to three months, average dose equals 375 mg/day) was associated with a marked reduction in hyperglycemia and an increase toward normal in insulin binding to mononuclear cells. In conclusion, (1) mononuclear cells from nonobese, nonketotic, untreated adult diabetic patients with fasting hyperglycemia demonstrate a decreased ability to bind insulin due to decreased numbers of insulin receptors per cell; (2) treatment with an oral hypoglycemic agent is associated with a diminution in hyperglycemia and a return toward normal of insulin binding.