Abstract Objective: A high level of plasma homocysteine may be deleterious to vascular health. We therefore compared the effect of combinations of sequential oral and transdermal estradiol plus norethisterone acetate on plasma homocysteine. Design: Prospective, randomized study. Setting: Outpatient department of obstetrics and gynecology in a university hospital. Patient(s): Forty-two healthy, nonsmoking postmenopausal women starting hormone replacement therapy (HRT) to control climacteric symptoms. Intervention(s): In a randomized order, the women started using either oral HRT (2 mg of estradiol on days 1–12, 2 mg of estradiol plus 1 mg of norethisterone acetate (NETA) on days 13–22, and 1mg of estradiol on days 23–28; n = 21) or transdermal HRT (50 μg/d of estradiol on days 1–28 and 250 μg/d of norethisterone acetate on days 15–28, n = 21) for 1 year. Main Outcome Measure(s): Fasting plasma levels of homocysteine were measured before the treatment and during the combined estradiol-plus-NETA phases of the sixth and 12th treatment cycles. Result(s): Basal homocysteine levels in the oral group (8.2 ± 3.1 μmol/L, mean plusmn;SD) and transdermal group (8.7 plusmn; 1.8 μmol/L, mean plusmn;SD) were not affected by the estradiol-plus-NETA combination. Conclusion(s): Neither an oral nor a transdermal combination of sequential estradiol and NETA causes significant changes in plasma homocysteine in Finnish postmenopausal women with normal baseline homocysteine levels.