Non-insulin-dependent diabetes mellitus (NIDDM) is a genetic disorder characterized by two major pathogenic processes: reduced insulin action and a relative or absolute decrease in plasma insulin concentrations. We studied 116 nondiabetic siblings from 45 families to determine if in vivo insulin action showed any aggregation among siblings. Subjects were Pima Indians from the Gila River Indian Community in Arizona who, as a group, have the highest reported incidence and prevalence of NIDDM in the world. In vivo insulin action was determined by the euglycemic-clamp technique at two rates of insulin infusion in each subject with resulting mean plasma insulin concentrations of 119 and 1938 microU/ml. After adjustment for age, sex, and degree of obesity, there was significant aggregation among siblings of in vivo insulin action at the high insulin infusion rate (P less than or equal to .0001). Family membership independently accounted for approximately 34% of the variance in this measure of insulin action. Glucose uptake at the lower insulin infusion rate also showed familial aggregation (P less than .01), with family membership independently accounting for approximately 15% of the variance of this measurement. We conclude that in vivo insulin action is a familial characteristic. The familial component of insulin action occurs in addition to the effects of obesity, age, and sex on insulin action. Therefore it is not sufficient to simply know that an individual is lean or obese to predict his/her in vivo insulin resistance, because it must also be known whether he/she is from an insulin-resistant or insulin-sensitive family.(ABSTRACT TRUNCATED AT 250 WORDS)