The ability of insulin to stimulate tissue glucose uptake and lower plasma FFA concentrations was quantified in 12 individuals with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM), further subdivided into obese and nonobese subjects. Measurements were made during 5-h glucose clamp studies, carried out at plasma insulin concentrations of about 10 μU/ml (0–150 min) and about 60 μU/ml (150–300 min). Differences between the patient groups were compared by two-way analysis of variance. The ability of insulin to either suppress plasma FFA concentrations or stimulate glucose uptake was significantly reduced (P < 0.001) in patients with NIDDM, and this was true of both the obese and nonobese groups. The defect in the ability of insulin to suppress plasma FFA concentrations in patients with NIDDM was more apparent at the lower insulin concentration, whereas resistance to insulin-stimulated glucose uptake in NIDDM was more dramatic at the high insulin concentration. Finally, a significant correlation (r = −0.67; P < 0.001) between insulinstimulated glucose uptake and plasma FFA concentration was found in the entire group. These data emphasize the fact that patients with NIDDM are resistant to multiple actions of insulin, and that the magnitudes of the defect in insulin suppression of plasma FFA levels and stimulation of tissue glucose uptake are roughly comparable.