Polymorphism of the angiotensin-I-converting enzyme (ACE) gene is associated with variations in serum ACE activity and the incidence of cardiovascular disease. Whether a similar association exists with cardiological syndrome X (chest pain, positive ECG exercise test, and normal angiography) is unclear. As ACE activity affects vascular tone, it could be involved in the pathogenesis of this syndrome. We measured serum ACE activity in 18 postmenopausal women with syndrome X and in 18 healthy controls matched for age, adiposity, and menopausal status. The relationship of ACE activity to coronary heart disease risk factors was also examined within these groups. Serum ACE activity did not differ significantly between women with syndrome X and controls. Neither blood pressure, serum total cholesterol, triglyceride, nor high density lipoprotein subfraction 2 cholesterol was associated with ACE activity in either patient group. However, serum high density lipoprotein cholesterol, high density lipoprotein subfraction 3 cholesterol, and apolipoprotein-A-I and -A-II were inversely associated with ACE activity in women with syndrome X, but not in controls. Insulin sensitivity, fasting plasma glucose, insulin, and C-peptide as well as their postglucose challenge concentration profiles were not significantly associated with ACE activity in either group. We conclude that serum ACE activity and, consequently, ACE polymorphism are not associated with syndrome X and are largely independent of metabolic risk factors in these women.