The aim of the present study was to examine the effects of hormone replacement therapy on homocysteine and its relationship with atherosclerotic changes. Twenty Wistar albino rats were deployed in the study. An artificial menopause was created. Rats were randomly assigned to 2 groups. The first group received 6 cycles of 0.01 mg/kg/day conjugated equine oestrogen and the second group received the same dose of placebo. After the treatment, vitamin B-12, folate and homocysteine levels were measured. Carotid arteries were removed for histopathological examination of vascular effects. Homocysteine levels were 3.35 +/- 0.22 and 2.28 +/- 0.12 mu mol/l, vitamin B-12 levels were 699 +/- 87.51 and 631 +/- 97.85 pg/ml and folate levels were 71.83 +/- 4.03 and 84.79 +/- 6.58 ng/ml in Groups 1 and 2, respectively. Statistical analyses revealed no significant differences between Group 1 and Group 2 with regard to vitamin B12 and folate levels. Homocysteine was found to be significantly elevated in Group 1 (P=0.001). Histopathological examination did not reveal any pathological finding in vascular sections in either group. Even though postmenopausal HRT is not used as a means of cardiovascular protection, it is the only treatment available for vasomotor symptoms and prevention of urogenital atrophy during menopause. Until the relationships between menopause, HRT, homocysteine, folate and vitamin B12 are clearly elucidated with more comprehensive studies, including all the details leading to plasma homocysteine increment in homocysteine metabolism, we recommend that menopausal women should be provided with accurate information and risk/benefit analysis on HRT treatment and the decision should be made by the patient.