The metabolically active form of vitamin D, 1,25-(OH)2D3, is involved in the regulation of insulin level. Because the serum group-specific component (Gc) binds vitamin D, it is worth knowing whether differences in basal insulin levels are associated with Gc genotype. Such differences would warrant further investigation to clarify whether selection maintains Gc polymorphism through differential risk of Gc genotypes to diseases that involve insulin. Blood samples were collected in a study designed to address issues in the etiology of non-insulin-dependent diabetes mellitus in Amerindians. Fasting insulin levels and Gc genotype (including subtypes of Gc1) were determined for 144 adult Dogrib Indians of the Northwest Territories, Canada. Hierarchical regression of log10 transformed fasting insulin on age and adiposity within each sex showed that age had no effect on insulin level, but adiposity as measured by the body mass index (BMI) had a very highly significant effect. Analysis of covariance of log10 fasting insulin by sex, by Gc genotype and with adjustment for the effects of the covariate, BMI, was very highly significant. All interaction terms in the model were nonsignificant. The only variable that had a significant effect after adjustment for the BMI was Gc genotype (F4,133 = 3.71; P = 0.007). Covariance analysis was repeated on a subset of the sample (124 people). The reduced data set excluded all individuals who had, on at least one occasion, abnormal response to oral glucose challenge [impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM]). Again, after correction for the effects of the BMI, only Gc genotype had a significant effect on fasting insulin level (F4,113 = 2.61; P = 0.040). Homozygotes for Gc 1F-1F had the lowest measures of fasting insulin.