An Alu-repeat polymorphism in the gene coding for tissue-type plasminogen activator has been described recently, and it has been hypothesized that this polymorphism may predict risk of coronary thrombosis. In a prospective cohort of nearly 15,000 apparently healthy men, presence of an Alu-repeat insertion/deletion (I/D) polymorphism in the gene coding for tissue-type plasminogen activator was determined among 369 study participants who subsequently suffered a first myocardial infarction (cases) and among a group of 369 age- and smoking-matched study participants who remained free of reported cardiovascular disease during follow-up (controls). The distributions of the II, DI, and DD genotypes of the tissue-type plasminogen activator polymorphism among men who subsequently suffered myocardial infarction (0.30, 0.50, 0.21) were virtually identical to those who remained free of disease (0.29, 0.50, 0.21; P = .9). There was no evidence of association between the Alu insertion polymorphism and risks of future myocardial infarction in models assuming either allelic recessive (relative risk, 1.05; 95% confidence interval, 0.8 to 1.4, P = .8) or allelic dominant (relative risk, 1.04; 95% confidence interval, 0.7 to 1.5, P = .8) modes of inheritance, nor were associations found in analyses stratified by age, family history, hypercholesterolemia, or the presence of other risk factors for premature coronary disease. Multivariate analysis had no important effects on these relationships. In this cohort of middle-aged US men, the presence of the insertion allele of the Alu-repeat polymorphism of the tissue-type plasminogen activator gene is not associated with future risks of myocardial infarction.