This study's objective was to determine whether there is familial clustering of insulin sensitivity (S_I) or insulin-independent glucose uptake (S_G), which would be evidence that they are genetically determined traits. Outpatients had a 3-h intravenous glucose tolerance test. Nondiabetic individuals (n = 183), ranging in age from 16 to 60 yr, were from 105 families that had 2 parents with non-insulin-dependent diabetes mellitus. Of these families, 62 contributed 1 offspring, 21 contributed 2, 13 contributed 3, 6 contributed 4, and 2 and 1 contributed 5 and 6, respectively. The minimal model of glucose disposal and the glucose and insulin values from the intravenous glucose tolerance tests were used to estimate S_I and S_G. The intraclass correlation coefficient was used to compare the within-family variability of S_I and S_G with the respective between-family distributions. The intraclass correlation coefficients were 0.26 (P = 0.008) for S_I and 0.081 (P = 0.45) for SG. S_I and S_G were uncorrelated (r = −0.059, P = 0.42). The intraclass correlation of S_I could not be explained by familial clustering of fasting insulin or ideal body weight. Finally, the 10 families with the lowest values of S_I had a significantly higher within-sibship variability of S_I than the other 33 families (P < 0.001, F test). S_I but not S_G showed familial clustering, which is consistent with a polygenic determinant of S_I. In addition, a large within-family variability of S_I in some families is compatible with a major gene effect with a dominant mode of inheritance. Thus, defects in genes affecting S_I are plausible candidates for determinants of familial clustering of non-insulin-dependent diabetes mellitus.