Insulin resistance is thought by many to be the primary defect that results in non-insulin-dependent diabetes mellitus (NIDDM). An implication of this theory is that prediabetic persons have higher serum insulin levels than normal subjects. We assessed serum insulin concentrations in a cohort of 1497 nondiabetic Mexican Americans, a population at high risk for NIDDM, according to whether their parents or siblings had diabetes. It was assumed that prediabetic persons would be more likely to have strong family histories of diabetes. We found a stepwise increase in fasting insulin levels in nondiabetics with neither, one, or both parents with diabetes (69.8, 77.8, and 94.6 pmol per liter, respectively; P = 0.002). Similar results were observed for insulin sum (the total of insulin concentrations in the fasting state and at 30, 60, and 120 minutes after a 75-g oral glucose load). The differences in insulin sums according to family history remained statistically significant in analyses of covariance, which controlled for variations in body-mass index, body-fat distribution, and level of blood glucose. Subjects without diabetes who had a diabetic sibling had higher fasting concentrations of insulin than subjects without a diabetic sibling (83.2 vs. 69.6 pmol per liter), but the difference was not statistically significant. We conclude that prediabetic persons, who would be expected to be more numerous in kindreds with progressively stronger family histories of diabetes, have hyperinsulinemia. This supports the insulin-resistance hypothesis.