Elevated plasma cell membrane glycoprotein 1 (PC-1) expression and the frequent PC-1 K121Q polymorphism have recently been associated with insulin resistance. Since insulin resistance represents an important risk factor for atherosclerotic vascular disease and myocardial infarction, we investigated the involvement of the PC-1 K121Q polymorphism in the development of myocardial infarction. We analyzed two independent series of cardiovascular patients at a defined end-point of atherosclerotic vascular disease (those having suffered myocardial infarction) for the PC-1 K121Q mutation by a newly developed mutagenic separated PCR assay. In both patient groups the presence of the Q allele was significantly associated with younger age at the time of first myocardial infarction, suggesting a more rapid progression of endothelial dysfunction. In a multivariate analysis carriers of the 121Q allele from Vienna and from Central Germany exhibited a 2.6- and a 4.2-increased odds, respectively, for suffering myocardial infarction within the first tertile of age (<51 and <48 years, respectively). Our data indicate that the PC-1 121Q allele might predispose independently of other well established risk factors for early myocardial infarction. Testing for the PC-1 K121Q polymorphism might be valuable in patients with a family history of atherosclerotic vascular disease and myocardial infarction.