We assessed endogenous endothelial-dependent fibrinolysis in 99 subjects with coronary artery disease (CAD) documented by angiography and in 28 control subjects with normal coronary arteries on angiography. We used specific, sensitive assays for plasma tissue-type plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor (PAI) activity, plasminogen, and alpha-2 plasmin inhibitor (alpha-2 PI). Mean PAI activity was significantly higher, and mean t-PA activity after venous occlusion of the upper arm (a standard test of the capacity of vascular endothelium to release t-PA) was significantly lower in subjects with CAD than in subjects with normal coronary arteries. The mean increment in t-PA antigen after venous occlusion was significantly lower than normal in subjects with CAD with onset of symptoms before age 45 years. Subjects with CAD had a significantly increased mean plasma fibrinogen level compared with control subjects, and a significant positive correlation was observed between PAI activity and plasma fibrinogen in subjects with CAD. No significant abnormalities of plasminogen or alpha-2 PI were observed in any subset of subjects with CAD. These data support an association between impaired fibrinolysis and CAD, with contributions from both increased PAI activity and in younger subjects from reduced endothelial t-PA release.