The plasma homocysteine (Hcy) concentration is an independent risk factor for cardiovascular disease (CAD). The increase of plasma Hcy levels at menopause suggests a close relationship between Hcy metabolism and estrogen status and proposes one of the mechanisms through which menopause unfavorably affects CAD risk in women. It has been suggested that hyperhomocysteinemia may promote the production of hydroxyl radicals, through Hcy autooxidation and thiolactone formation. Some investigators have suggested that Hcy may cause atherosclerosis by damaging the endothelium either directly or by altering oxidative status during aging. In this study, the effects of hormone replacement therapy (HRT) on plasma levels of endogenous malondialdehyde (MDA) formation, Hcy and total thiol (t-SH) were investigated in healthy postmenopausal women who received HRT for 1 year. We also determined the enzymatic antioxidant activities, such as superoxide dismutase (SOD) and glutathione-S transferase (GST). We hypothesized that HRT would relate positively with antioxidant status. A number of 80 unrelated healthy postmenopausal women (aged 45-56 years), and 40 unrelated healthy control subjects (aged 30-45 years) were included in the study. Postmenopausal women were selected from the outpoint clinic of the Department of Obstetrics and Gynecology. All participants underwent clinical, biochemical and hormonal screening procedures including gynecologic and physical breast examination. Postmenopausal women were divided into two groups. HRT group involved 45 healthy postmenopausal women who were receiving hormone replacement therapy for 1 year: oral estradiol valerate 2 mg/day plus continuous cyproterone acetate 1 mg/day. NHRT group included 35 healthy postmenopausal women who received orally placebo but not received HRT. In the samples, levels of MDA, t-SH and activities of GST and SOD were measured before and after treatment. There was no significant change in plasma Hcy levels between HRT and NHRT groups. However, Hcy concentration is significantly elevated in both NHRT and HRT groups as compared to control. MDA and t-SH correlated significantly with Hcy (p=0.388 and p= 0.478, respectively) content and there was a significant negative correlation between E2 level and GST activity (p= -0.425) in HRT group. SOD and HDL-C correlated significantly with t-SH level (p=0.339 and p= 0.336, respectively) in plasma after HRT in women. Our data have supported the hypothesis that elevated Hcy levels stimulate production of hydroxyl radicals. In addition, our findings are important as it indicates that HRT may reduce oxidative stress in postmenopausal women.