Serum retinol binding protein 4 (RBP4) was recently described as a new adipokine that reduced peripheral and hepatic insulin sensitivity and increased hepatic gluconeogenesis. The RBP4 gene maps to 10q23-24, near a region linked to T2DM in Caucasian and Mexican American populations. Hence, sequence variants that alter RBP4 expression or function could increase T2DM susceptibility and reduce insulin sensitivity. We screened the 6 exons, flanking intronic sequence, and 5' and 3' flanking sequences in 48 Caucasian and 48 African American subjects. We identified 21 SNPs, of which 8 were unique to the African American population. Additional public database SNPs were chosen for regions not screened. We selected SNPs for typing based on frequency, linkage disequilibrium, and location in a putative functional or conserved region. We typed 10 SNPs in 191 Caucasians with T2DM and a family history of T2DM, and 188 euglycemic controls with no family history of diabetes. We similarly typed 14 variants in 182 controls and 353 diabetic individuals of African American ancestry. No single variant was associated with type 2 diabetes in either population (p>0.15 in African Americans, p>0.09 in Caucasians), but a haplotype of 8 common SNPs in Caucasians was significantly increased in type 2 diabetics compared with controls (0.137 vs. 0.076, p=0.008). Furthermore, SNPs -804 and +9476 were associated with reduced insulin secretion, (p=0.01 and 0.001, respectively), and SNP +390 with reduced insulin sensitivity (p=0.0005) in Caucasians. Our data suggest that noncoding SNPs may increase diabetes susceptibility in Caucasians and may contribute to insulin resistance and reduced insulin secretion.