Both insulin resistance and decreased insulin secretion have been hypothesized to be precursors of non-insulin-dependent diabetes. An elevated proinsulin concentration reflects abnormal proinsulin processing and could indicate abnormal insulin secretion. We examined fasting insulin (measured by a radioimmunoassay that does not cross-react with proinsulin), as a marker of insulin resistance, and proinsulin and the fasting proinsulin-to-insulin ratio, as markers of impaired proinsulin processing, in 597 nondiabetic Mexican-Americans from the San Antonio Heart Study. Fasting insulin, proinsulin, and the fasting proinsulin-to-insulin ratio were higher in subjects with a parental history of diabetes than in subjects without such a history. These differences remained statistically significant after adjustment for obesity, body fat distribution, and glucose tolerance. A parental history of diabetes in nondiabetic Mexican-Americans is associated with an increase in fasting specific insulin and a disproportionate increase in proinsulin relative to insulin. These data suggest that both increased insulin resistance and abnormal processing of proinsulin are present in offspring of parents with diabetes.