Endogenous tissue-type plasminogen activator (tPA) has been hypothesised to be a marker of baseline fibrinolytic capacity. We therefore tested whether tPA antigen is associated with the occurrence of future myocardial infarction (MI) among apparently healthy individuals. tPA antigen concentrations were measured at baseline in plasma samples from 231 apparently healthy men from the Physicians' Health Study cohort who later developed MI, and in an equal number of controls matched for age and smoking habit who remained free of reported cardiovascular disease during a follow-up of 60.2 months. In crude matched-pair analyses, baseline concentrations of tPA antigen were higher in cases than controls (p = 0.03) and strongly associated with risk of future MI. Specifically, the relative risks of developing a first MI from lowest (referent) to highest quintiles of tPA antigen were 1.00, 1.27, 1.75, 1.88, and 2.81 (p for trend 0.0008, 95% CI for the relative risk in the fifth as compared with first quintile 1.47 to 5.37, p = 0.002). Analyses which adjusted for risk factors that affect progression of atherosclerosis, particularly HDL-cholesterol, abolished the statistical significance of this association, a finding which suggests that elevations of tPA antigen are a result rather than a cause of atherosclerotic coronary disease. These prospective data suggest that endogenous tPA concentrations increase as a consequence of important preclinical atherosclerosis and therefore may be a marker for risk of future MI.