Changes in insulin receptor (IR) of red blood cells in 47 patients with noninsulin dependent diabetes mellitus (NIDDM) were compared with those of 28 normal controls, with respect to the clinical significance of the measurement of insulin receptors and the mechanism of NIDDM. The levels of high and low affinity IR in the 47 patients with NIDDM were lower than those of normal controls and were prominent in untreated newly diagnosed NIDDM patients. Hyperinsulinemia was not found in these patients, indicating that the low IR activity is a primary defect, not caused by the down regulation mechanism. In patients with insulin dependent diabetes mellitus (IDDM) the level of high and low affinity IR were higher than those of the normal controls, but decreased markedly after insulin therapy, indicating that the up regulation is attributable to the high IR levels, other than the primary IR defect.