In Caucasian subjects, an insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is associated with coronary artery disease (CAD) and fatal myocardial infarction. The underlying mechanism(s) of this association is not fully understood. Pima Indians have a low incidence of nonfatal and fatal CAD despite a high prevalence of diabetes. In Pima Indians, circulating ACE levels are related to ACE genotype, but the frequency of the D allele is significantly lower than in Caucasians. A lower frequency of the D allele may underlie a low risk of CAD in this population. We examined the relationship of the ACE genotype and plasma ACE level with electrocardiographic evidence of CAD (Tecumseh criteria), hypertension, and metabolic variables associated with insulin resistance in 305 (146 men and 159 women aged 47+/-9.0 years) Pima Indians characterized for the ACE I/D genotype. The distribution of ACE genotypes was unrelated to diabetes and obesity. Fasting plasma insulin, plasminogen activator inhibitor-1 (PAI-1) activity, plasma triglyceride concentrations, and systolic (SBP) and diastolic (DBP) blood pressure were not significantly different between the three ACE genotypes among nondiabetic and diabetic subjects. There was no significant association of ACE genotype with electrocardiographic evidence of CAD or with hypertension. Plasma ACE concentrations were not significantly different between nondiabetic and diabetic subjects (median, 77 [range, 21 to 1691 v 83 [7 to 238] IU/mL, P=NS). In all subjects, plasma ACE levels were associated weakly with plasma triglyceride (partial r=.20, P < .01) and total cholesterol (partial r=.13, P <.03) concentrations, but not with fasting plasma insulin or PAI-1 activity. In diabetic subjects, ACE levels were related to fasting plasma glucose concentrations (partial r=.15, P=.07). These findings would suggest that ACE gene I/D polymorphism is unlikely to be a major determinant of susceptibility to CAD in Pima Indians. Plasma ACE levels, but not ACE genotype, correlated with lipids, plasma glucose, and blood pressure, suggesting that elevated plasma ACE levels may contribute to the link between insulin resistance and CAD disease or may be a consequence of it.