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, HDL2 cholesterol, HDL3 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), HDL2 cholesterol (r = -.1632, P < .0005), and HDL3 cholesterol (r = -.0927, P = .019). 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 = .0219, 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 HDL2 and HDL3 cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)