Lipid fractions of native plasma and of high-density lipoprotein (HDL) were analyzed, and the clotting times of native platelet-rich and -poor plasma were recorded in patients with coronary artery disease and age-matched control subjects not taking any medication known to alter plasma lipid levels, coagulation, or platelet aggregation. Patients with coronary artery disease had lower HDL cholesterol and particularly HDL phospholipids but elevated HDL triglycerides, plasma triglycerides and diglycerides, and fibrinogen. Plasma lysolecithin was diminished. Accelerated coagulation was observed in native plasma and may be related to these changes in plasma lipids. The HDL content in cholesterol may be less relevant than that in phospholipids, which, because of their amphiphilic properties, may be essential for the removal and transport of hydrophobic cholesterol. The lower lysolecithin levels also suggest diminished esterification of cholesterol and reduced degradation of phospholipids, which may add to the poor lysability of platelet-rich and thus phospholipid-rich thrombi. Coagulation inhibition may be related to HDL phospholipids: in control subjects they correlated directly with clotting times of platelet-rich and -poor plasma and inversely with fibrinogen. In contrast, the enhanced thrombus formation in coronary artery disease may be related to altered HDL and plasma phospholipids, in particular to increased phosphatidylethanolamine. These adverse changes, particularly diminished HDL phospholipids, may result in increased deposition and reduced degradation and transport of lipids from arteriosclerotic lesions and thrombi and may therefore be significant in the development of coronary artery disease.