Susceptibility to non-insulin-dependent diabetes mellitus (NIDDM) is largely genetically determined. In Pima Indians, obesity, insulin resistance, and a low acute insulin response (AIR) to an intravenous glucose infusion are each predictors of the disease. To ascertain whether these phenotypes are genetically determined, we estimated their familiality in nondiabetic Pima Indians with a maximum-likelihood method. Percentage body fat (PFAT) was highly familial (h2=. 76), whereas waist/thigh circumference ratio (W/T ratio) was not significantly familial after controlling for PFAT (h2=. 16). AIR was also highly familial (h2=. 80 at 10 min), even after controlling for PFAT and insulin action (h2=. 70). Insulin action at physiologic plasma insulin concentrations was familial (h2=. 61) but less so after controlling for PFAT and W/T ratio (h2=. 38). At maximally stimulating insulin concentrations, insulin action was familial (h2=. 45) and was less influenced by controlling for PFAT and W/T ratio (h2=. 49). We conclude that in Pima Indians (1) PFAT and AIR are highly familial traits,(2) central distribution of fat is not a familial trait when controlled for PFAT,(3) 38%-49% of the variance in insulin action, independent of the effect of obesity, is familial, and (4) PFAT, AIR, and insulin action are useful traits to study genetic susceptibility to NIDDM. Because genetic parameter estimates are applicable only to the populations from which they were estimated, it is important to determine whether these estimates of familialities in Pima Indians can be confirmed in other populations before the utility of these traits in searching for NIDDM susceptibility genes in those populations can be fully advocated.