The angiotensin-converting enzyme (ACE) is a key factor in the production of angiotensin II and in the degradation of bradykinin, two important peptides involved in vascular physiology. Plasma and cellular ACE levels in humans are influenced by an insertion (I)/deletion (D) polymorphism of the ACE gene, the ACE I/D polymorphism. The D allele has a frequency of approximately 0.53 in Caucasian populations and is codominantly associated with higher levels of ACE. We have studied this polymorphism in a large multicenter case-control study (the ECTIM study) and found that the D allele was associated with a parental history of fatal myocardial infarction (MI) in the controls and was more frequent in male patients with MI than in controls. This case-control difference was compatible with a codominant effect of allele D on the risk of MI with relative risks of 1.57 for DD vs II and 1.26 for ID vs II (test for trend p < 0.003). In subjects at low risk of MI (plasma ApoB < 1.25 g/l and body mass index < 26 kg/m2), the relative risk of DD vs ID + II was 2.7 (p < 0.0005). The results were very homogeneous in the four populations included in the study. In a family study, using linkage-segregation analysis, we have shown that the ACE I/D polymorphism is a marker for an unknown functional polymorphism (ACE S/s) which appears to be a new independent risk factor for MI.