Hyperinsulinemia, a major indicator of insulin resistance, may exert its influence on the risk of coronary artery disease partially through disturbances of the hemostatic system. The relations of fasting insulin concentrations with the degree of coronary atherosclerosis, other coronary risk factors (including some markers of the insulin resistance syndrome such as body mass index and triglyceride), markers of inflammation, and hemostatic factors were investigated in 1484 patients with angina pectoris. Mean insulin levels were higher in patients with one or more coronary vessel stenoses than in those without (9.9fiU/mLcompared with 9.0fiV/mh,p<.0001). However, the association with the presence of vessel stenoses was stronger in patients with a previous myocardial infarction than in those without. Insulin increased markedly (p<.0001) and independently of other risk factors with age, body mass index, triglyceride concentration, and markers of inflammation, such as white blood cell count and C-reactive protein. The strongest relations between insulin and hemostatic factors were observed with fibrinolytic variables, particularly plasminogen activator inhibitor-1 (PA1-1) levels (r=.44,p<.0001). This relation decreased somewhat (r=.29) after simultaneous adjustment for markers of the insulin resistance syndrome, mainly body mass index and triglycerides, but not after adjustment for markers of inflammation. Therefore, we propose that increased PAI-1 levels, which are essentially related to the classic metabolic aspect of the insulin resistance syndrome, have to be included in this syndrome. Insulin concentrations were also significantly related to a lesser extent with hemostatic variables that are considered as acute-phase markers, such as fibrinogen, von Willebrand factor, and factor VIII: c; these correlations were independent of joint associations with other coronary risk factors, including body mass index and triglyceride. Simultaneous adjustments for markers of inflammation substantially reduced the fibrinogen relation to insulin but only slightly modified those between insulin and von Willebrand factor and factor VIII:c. These results indicate that the insulin-fibrinogen relation is more related to the accompanying acute-phase reaction, whereas the link between insulin and von Willebrand factor and factor VIII: c may be due to nonspecific endothelial cell damage.