Few studies have examined the association of SNPs in the adiponectin (ADIPOQ) and adiponectin receptor 1 and 2 (ADIPOR1, ADIPOR2) genes with the euglycemic clamp, i.e. the gold standard measure of insulin sensitivity. The association of comprehensive tag SNPs in these genes with insulin sensitivity was examined in a cohort of adolescents and their parents. Probands and siblings (n=441, mean age=17.9 years) were recruited along with their parents (n=262, mean age=47.9 years). Typed SNPs included 21 SNPs in ADIPOQ, 7 SNPs in ADIPOR1, and 13 SNPs in ADIPOR2. Mixed model linear regression was used to test the association of SNPs with euglycemic-clamp derived insulin sensitivity. All analyses were stratified by race. After corrections to account for multiple testing and the linkage disequilibrium structure of the genes, one SNP in the ADIPOQ gene (rs822393) was significantly associated with insulin sensitivity in white subjects. In whites, six SNPs in ADIPOQ, one SNP in ADIPOR1 and one SNP in ADIPOR2 were associated with insulin sensitivity at the P<0.05 level. In African Americans, two SNPs in ADIPOR1 were associated with insulin sensitivity at the P<0.05 level. These results suggest that a variant in the ADIPOQ gene influences levels of insulin sensitivity and age may modify the effects of this variant. There are several other variants in ADIPOQ, ADIPOR1, and ADIPOR2 that may influence insulin sensitivity and these variants should be further investigated in other populations.