Although a strong clinical association exists between obesity and NIDDM, previous studies have failed to confirm a significant relationship between the degree of obesity and the insulin resistance of NIDDM. We examined the impact of obesity on insulin-mediated glucose metabolism in 25 patients with NIDDM, whose BMI ranged from 20.8 to 36.9 kg/m2, during insulin infusions of 0.4, 1.0, and 10 microU/kg min using the glucose clamp technique. Rates of glucose disposal and HGP were compared in 14 of the diabetic patients with 19 nondiabetic control subjects of similar sex, age, and weight distribution. We found an inverse correlation between BMI and the glucose infusion rate necessary to maintain euglycemia during the first two of three insulin infusions (r = -0.63, P < 0.001, r = -0.57, P < 0.01, and r = -0.36, P = 0.08). Glucose disposal was correlated with BMI during the 1.0 mU/kg min insulin infusion (r = -0.57, P < 0.05), and glucose production was correlated at the 0.4 mU/kg min infusion (r = 0.69, P < 0.01). We concluded that obesity diminishes the insulin sensitivity of both hepatic and peripheral tissues in patients with NIDDM. The exacerbation of the insulin resistance of NIDDM by obesity indicates why weight reduction is an effective treatment for the obese NIDDM patient.