The fibrinolytic system may play a role in the pathogenesis of coronary heart disease (CHD), but existing prospective studies have not consistently shown an independent association between fibrinolytic factors and CHD. None has reported an association between plasminogen and CHD incidence. In the prospective Atherosclerosis Risk in Communities (ARIC) Study of middle-aged adults, we examined the association of incident CHD with several fibrinolytic factors: tissue plasminogen activator antigen, plasminogen activator inhibitor-1, plasminogen, and fibrin fragment D-dimer as well as a marker of coagulation activation (prothrombin fragment F1.2). We measured these in stored baseline plasma samples of 326 subjects who developed CHD and, for comparison, a stratified random sample of the entire cohort (n=720). Tissue plasminogen activator and plasminogen activator inhibitor-1 antigen levels were associated positively with CHD incidence in analyses adjusted for age, race, and sex but were not associated with CHD after adjustment for other risk factors. Plasminogen and D-dimer levels were associated positively and independently with CHD incidence; the multivariable-adjusted relative risks (95% CIs) for the highest versus lowest quintiles were 2.20 (1.2 to 4.2) for plasminogen and 4.21 (1.9 to 9.6) for D-dimer. F1.2 was not associated with CHD incidence. Our findings lend support for a link between fibrinolytic factors and CHD incidence. A positive association between plasminogen and CHD is seemingly opposite the direction expected but may reflect a compensatory response to impaired plasminogen activation in subjects prone to CHD.