Annexin V has phospholipid-binding capacity and plays a potent antithrombotic role. Recently, a C to T transition has been described in the Kozak region of this gene, affecting the nucleotide preceding the initiation ATG codon. We have developed a simple method to detect this genetic change, showing by analysis of 580 Mediterranean white subjects that the -1C to T transition (-1C>T) is a common polymorphism (allele frequency, 0.121). This polymorphism is in linkage disequilibrium with a new C>G polymorphism located 27 bp downstream in intron 2. We show that -1C/C carriers presented significantly lower plasma levels of annexin V than -1C/T subjects (0.45 +/- 0.20 ng/mL versus 0.73 +/- 0.28 ng/mL, respectively; P =.02). In vitro transcription/translation experiments support that the -1T allele increases translation efficiency. The clinical relevance of the -1C>T change was investigated in consecutive patients with nontraumatic spontaneous intracranial hemorrhage (n = 225), deep venous thrombosis (n = 151), and coronary heart disease (n = 101). Finally, we also studied 166 survivors of an acute myocardial infarction occurring at age of 45 or less. This polymorphism seems to have a minor effect in bleeding disorders, but to play a protective role against early myocardial infarction, reducing by 2-fold the risk of developing the disease (P =.006; odds ratio, 0.51; 95% confidence interval, 0.30-0.85).