Formation of an occlusive thrombus by exposure of tissue factor (TF) to circulating blood and subsequent triggering of coagulation by TF-activated factor VII (FVIIa) complexes on ruptured atherosclerotic plaques is thought to be a key event in myocardial infarction. Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of TF-induced coagulation in which the anticoagulant function most probably is restricted to free TFPI in human plasma. The present study was undertaken to assess the interrelations between serum lipids and components of TF-induced coagulation in 234 apparently healthy men aged 36-56 years recruited from the general population. Plasma free TFPI antigen (Ag) was positively correlated (P < .001) with total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein B (apoB-100), fibrinogen, total amount of FVII (FVIIam), coagulation activity of factor VII (FVIIc), and FVIIa. The significant predictors for free TFPI Ag were total cholesterol, triglycerides, fibrinogen, FVIIc, and age, which explained 33% of the plasma variation in free TFPI Ag assessed by multiple regression analysis. A highly significant (P < .0001) linear trend for increase in atherogenic lipids (i.e., total cholesterol and triglycerides), FVII (i.e., FVIIc and FVIIa), and fibrinogen across quartiles of TFPI Ag was demonstrated after adjustment for confounders. These findings may indicate a compensatory increase in plasma free TFPI with lipid and hemostatic risk factors for atherothrombotic diseases in healthy middle-aged men.