OBJECTIVE: The objective of this study was to assess the relationship between putative markers of endothelial dysfunction (tissue plasminogen activator [t-PA] antigen and von Willebrand factor [vWF] antigen) and development of type 2 diabetes, as well as the role of inflammation, adipokines, hepatic function, and insulin resistance in modifying these relationships. RESEARCH DESIGN AND METHODS: This was a prospective study of 3,562 nondiabetic men aged 60-79 years followed up for an average of 7 years during which there were 162 incident cases of type 2 diabetes. RESULTS: Elevated t-PA (top third) was associated with a near threefold increase in risk of diabetes compared with the risk in those in the bottom third after adjustment for lifestyle factors and waist circumference (relative risk [RR] 2.98 [95%CI 1.79-5.00]; P(trend) < 0.0001); weaker but significant (marginal) associations were seen with vWF (1.24 [0.83-1.85]; P = 0.05 for trend). Both biomarkers of endothelial dysfunction correlated significantly with markers of inflammation (interleukin-6 [IL-6] and C-reactive protein [CRP]), hepatic function (gamma-glutamyl transferase [GGT]), and insulin resistance, with t-PA showing stronger associations with adiposity, hepatic function, and insulin resistance than vWF. t-PA was also significantly and inversely associated with adiponectin. Adjustment for IL-6, adiponectin, and GGT attenuated the association of incident diabetes with vWF (1.06 [0.71-1.60]), but the relationship seen with t-PA remained significant (adjusted RR 2.19 [1.29-3.70]). Subsequent adjustment for insulin attenuated the association further, but t-PA was still associated with a significant increase in risk (1.66 [0.96-2.85]; P(trend) = 0.02). CONCLUSION: t-PA antigen, but not vWF antigen, is independently associated with risk of type 2 diabetes.