The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE), the A1166C polymorphism in the angiotensin type 1 receptor (AT1R), and the M235T polymorphism of the angiotensinogen gene are associated with cardiovascular disease mostly in men. Few data are available on the effects of these genetic variations in postmenopausal women according to hormone replacement therapy (HRT) use. In this case-control study, we determine the frequency of mutant alleles in the ACE I/D, M235T and A1166C polymorphisms in postmenopausal Caucasian women with and without a diagnosis of acute coronary syndrome (ACS). Data from 198 women with ACS (63+/-10 years) and 149 controls (62+/-7 years) showed that ACE-DD genotype was more prevalent in women with ACS compared to controls (30% vs. 19%, P<0.05). There was no difference in genotype distributions for either the M235T or the A1166C polymorphisms between groups. The difference in ACE genotype distribution between ACS women and controls was driven by current HRT users with 30% of ACS and 15% of controls carrying the ACE-DD genotype (P<0.05). The oligenic combination of ACE-DD and M235T-TT genotypes was higher in ACS compared to controls. Among carriers of M235T-TT, 7% of ACS and 1% of controls also had the ACE-DD genotype, P<0.05. Thus, the ACE-DD genotype may be associated with ACS in postmenopausal women, particularly in HRT users.