Endothelial dysfunction may precede development of type 2 diabetes. We tested the hypothesis that elevated levels of hemostatic markers of endothelial dysfunction, plasminogen activator inhibitor-1 (PAI-1) antigen, and von Willebrand factor (vWF) antigen predicted incident diabetes independent of other diabetes risk factors. We followed 2,924 Framingham Offspring subjects (54% women, mean age 54 years) without diabetes at baseline (defined by treatment, fasting plasma glucose > or =7 or 2-h postchallenge glucose > or =11.1 mmol/l) over 7 years for new cases of diabetes (treatment or fasting plasma glucose > or =7.0 mmol/l). We used a series of regression models to estimate relative risks for diabetes per interquartile range (IQR) increase in PAI-1 (IQR 16.8 ng/ml) and vWF (IQR 66.8% of control) conditioned on baseline characteristics. Over follow-up, there were 153 new cases of diabetes. Age- and sex-adjusted relative risks of diabetes were 1.55 per IQR for PAI-1 (95% CI 1.41-1.70) and 1.49 for vWF (1.21-1.85). These effects remained after further adjustment for diabetes risk factors (including physical activity; HDL cholesterol, triglyceride, and blood pressure levels; smoking; parental history of diabetes; use of alcohol, nonsteroidal anti-inflammatory drugs, exogenous estrogen, or hypertension therapy; and impaired glucose tolerance), waist circumference, homeostasis model assessment of insulin resistance, and inflammation (assessed by levels of C-reactive protein): the adjusted relative risks were 1.18 per IQR for PAI-1 (1.01-1.37) and 1.39 for vWF (1.09-1.77). We conclude that in this community-based sample, plasma markers of endothelial dysfunction increased risk of incident diabetes independent of other diabetes risk factors including obesity, insulin resistance, and inflammation.