To elucidate the role of insulin receptor abnormality on the pathogenesis of non-insulin dependent diabetes mellitus (NIDDM), the autophosphorylative activity of erythrocyte insulin receptors was measured by a newly developed sandwich assay. Of 124 subjects who had a basal immunoreactive insulin level above 15μU/ml, five families were identified as insulin receptor kinase deficient. Two of these families were extensively studied by using a 75-g oral glucose tolerance test (OGTT). In these two families, the insulin receptor abnonmality was almost identical among family members, but family members exhibited different patterns of glucose levels in the OGTT. The subjects who showed a diabetic pattern in the OGTT were chanacterized by a deficiency of initial insulin secretion (ΔIRI/ΔBS at 30min less than 0.2). These results suggest that the incidence of a genetic insulin receptor abnormality in the NIDDM patients with basal hyperinsulinemia is around 5%. Moneover, simple insulin resistance may not be sufficient to cause clinically overt diabetes mellitus.