Elevated levels of endogenous tissue-type plasminogen activator (t-PA) appear to be a marker for preclinical atherosclerosis. At present, however, data describing potential relations between plasma t-PA level and established lipid risk factors for coronary atherosclerosis are sparse. To explore these potential relations, we measured plasma levels of t-PA antigen (t-PA:ag) in 633 apparently healthy men in the Physicians' Health Study as well as total cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2cholesterol, HDL, cholesterol, and apolipoproteins A-I, A-II, and B-100. Overall, plasma t-PA:ag levels were inversely correlated with HDL cholesterol (r=−.1616,p<.0005), HDL2cholesterol (r=−.1632,p<.0005), and HDL] cholesterol (r=−.O927, P=.O19). In stratified analyses, the inverse association between t-PA:ag and HDL cholesterol was present among frequent (P trend=.002) and infrequent (P trend=.004) consumers of alcohol as well as among the subgroups of frequent exercisers (P trend <.001), men in the lower half of body mass index (P trend=.001), and nonsmokers (P trend<.001). In contrast, there was no association between t-PA:ag and total cholesterol (r=.O219, P=.58), whereas relations of t-PA:ag with apolipoproteins A-I, A-II, and B-100 were minimal and of borderline significance. These data indicate that plasma levels of endogenous t-PA:ag are inversely related to HDL cholesterol as well as HDL2and HDL, cholesterol. Further research will be required to determine whether these modest but highly significant associations are due to a direct effect of lipids on fibrinolytic function or to independent associations of both t-PA:ag and lipids with atherosclerosis or are mediated by a third unmeasured variable.