We conducted a prospective, nested, case-control study of inflammatory markers as predictors of type 2 diabetes among 32,826 women who provided blood samples in 1989 through 1990 in the Nurses' Health Study. Among women free of diabetes, cardiovascular disease, or cancer at baseline, 737 had developed diabetes by 2000. Control women (n = 785) were selected matched on age, fasting status, race, and BMI for cases in the top BMI decile. Baseline levels of tumor necrosis factor (TNF)-alpha receptor 2, interleukin (IL)-6, and C-reactive protein (CRP) were significantly higher among case than control subjects (all P </= 0.001). After adjusting for BMI and other lifestyle factors, all three biomarkers significantly predicted diabetes risk; the odds ratios (ORs) comparing extreme quintiles were 1.64 (95% CI 1.10-2.45) for TNF-alphaR2, 1.91 (1.27-2.86) for IL-6, and 4.36 (2.80-6.80) for CRP (P for trend <0.001 for all biomarkers). In a multivariate model simultaneously including the three biomarkers, only CRP levels were significantly associated with risk of diabetes (OR comparing extreme quintiles of CRP = 3.99, P for trend <0.001). These data support the role of inflammation in the pathogenesis of type 2 diabetes. Elevated CRP levels are a strong independent predictor of type 2 diabetes and may mediate associations of TNF-alphaR2 and IL-6 with type 2 diabetes.