Thrombomodulin is an endothelial cell surface receptor that trans-formsthe procoagulant thrombin into an anticoagulant. A mutation inthe thrombomodulin gene is a potential risk factor for venous andarterial thrombosis.We screened a region within the coding sequence of the thrombo-modulingene by single-strand conformation polymorphism analysis(SSCP) in a pilot study of 104 patients with myocardial infarction and104 age, sex and race matched controls. We identified a 127 G to Amutation in the gene, which predicts an Ala25Thr substitution, in 2 outof 104 patients (1 man and 1 woman) with myocardial infarction but inno controls. We assessed the risk of myocardial infarction associatedwith the mutation in a larger “Study of Myocardial Infarctions Leiden”(SMILE). Among 560 men with a first myocardial infarction before theage of 70, 12 were carriers of the Ala25Thr substitution. In a controlgroup of 646 men, frequency-matched for age, seven were carriers ofthe Ala25Thr substitution. The allelic frequencies were 1.07% amongpatients and 0.54% among controls suggesting risk associated with themutation [odds ratio (OR) 2.0, 95% confidence interval (CI) 0.8-5.1].In patients aged below 50, the predicted risk was almost seven times in-creased(OR 6.5, CI 0.8-54.2). In the presence of additional risk factors,such as smoking and a metabolic risk factor, the predicted riskincreased to 9-fold (OR 8.8, CI 1.8-42.2) and 4-fold (OR 4.4,CI 0.9-21.3), respectively.While not conclusive, these results strongly suggest that theAla25Thr substitution is a risk factor for myocardial infarction, espe-ciallyin young men, and when in the presence of additional risk factors.