Linkage analysis has identified a susceptibility locus for type 2 diabetes mellitus (T2DM) on chromosome 1q21-q23 in several populations. Results from recent prospective studies indicate that increased levels of C-reactive protein (CRP), a marker of immune system activation, are predictive of diabetes, independent of adiposity. Because CRP is located on 1q21, we considered it a potential positional candidate gene for T2DM. We therefore evaluated CRP and the nearby serum amyloid P-component, APCS, which is structurally similar to CRP, as candidate diabetes susceptibility genes. Approximately 10.9kb of the CRP-APCS locus was screened for polymorphisms using denaturing high performance liquid chromatography and direct sequencing. We identified 27 informative polymorphisms, including 26 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion, which were divided into 7 linkage disequilibrium clusters. We genotyped representative SNPs in approximately 1300 Pima samples and found a single variant in the CRP promoter (SNP 133552) that was associated with T2DM (P=0.014), as well as a common haplotype (CGCG) that was associated with both T2DM (P=0.029) and corrected insulin response, a surrogate measure of insulin secretion in non-diabetic subjects (P=0.050). Linkage analyses that adjusted for the effect of these polymorphisms indicated that they do not in themselves account for the observed linkage with T2DM on chromosome 1q. However, these findings suggest that variation within the CRP locus may play a role in diabetes susceptibility in Pima Indians.