Interleukin-6 (IL-6, gene symbol IL6) is a proinflammatory cytokine. High circulating IL-6 levels have been associated with insulin resistance and greater risk of type 2 diabetes. Using a linkage disequilibrium (LD)-based approach, we sought to investigate the associations of the common polymorphisms comprehensively defining the genetic variability at the IL6 locus with diabetes risk. We conducted a case-control study of 2691 cases of type 2 diabetes (1692 women and 999 men) and 3237 control subjects (2238 women and 999 men) from the Nurses' Health Study and the Health Professional Follow-up Study. Pairwise LD analysis indicated that all the IL6 polymorphisms (rs2069827, rs1800797, rs1800795, rs1554606, rs2069849, rs2069861 and rs1818879) were in strong LD. We did not find significant associations between IL6 polymorphisms and the risk of type 2 diabetes in women or men, individually or in haplotypes. In addition, none of the IL6 polymorphisms was significantly associated with the plasma levels of IL-6 in the control subjects. Our meta-analysis of 5383 diabetes case and 12 069 controls indicated a null association between the best-studied 5' promoter polymorphism--174G>C (rs1800795)--and diabetes risk. Diversity in adiposity, age and sex could not account for the heterogeneity across different studies. In summary, the data in this study do not support substantial associations between the common polymorphisms in IL6 gene and circulating IL-6 levels and the risk of type 2 diabetes.