OBJECTIVE To compare the influence on lipid metabolism of two discontinuous, sequentially combined hormone replacement therapy (HRT) regimens. METHODS In an open, randomized study in 60 women, a full lipid profile including Lp(a) and liver function tests were assessed in a fasting state at the end of treatment cycles 6 and 12. Group A was treated with 2 mg oestradiol valerate (days 1-21) sequentially combined with 1 mg cyproterone acetate (days 12-21); group B was treated with a patch releasing 50 micrograms oestradiol daily, twice a week (3 weeks), sequentially combined with 20 mg dydrogesterone (days 12-21) orally. Statistical analysis by two-sided one-way analysis of covariance (covariable is baseline) for adjusted means of lipid parameters and rank transformation analysis for lipoprotein(a) (Lp(a)) was performed. RESULTS Both groups were statistically comparable. The trial was completed by 45 subjects. Protocol violations occurred in 3 cases. Twelve subjects, equally divided between the groups, dropped out mainly because of adverse reactions. Both treatments were equally effective in the treatment of climacteric complaints. Liver function tests during the treatment period were normal in both groups. In group A, a statistically significant (P < 0.05) decrease versus baseline was observed in the serum levels (adjusted means) of the following parameters after 6 and 12 treatment cycles: total cholesterol (TC)-5% and -7%, respectively; low-density lipoprotein cholesterol (LDL-C) -13% and -14%, respectively; low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C ratio) -16% and -18%, respectively. Triglycerides (TG) levels were significantly increased by 28% and nearly significantly (P = 0.07) by 25% after 6 and 12 treatment cycles, respectively. In group B, all lipid parameters (with the exception of apolipoprotein A-II which was significantly decreased after 12 treatment cycles) remained unchanged during therapy. Statistically significant differences for all aforementioned variables were found between the groups after 6 and 12 treatment cycles, respectively, with the exception of TC after 12 treatment cycles. After 6 treatment cycles, Lp(a) was decreased significantly (-18%) in group A as compared with baseline; after 12 months the decrease was -17% without reaching statistical significance. In group B, Lp(a) showed a slight but not statistically significant tendency to increase by 2% and 12% after 6 and 12 treatment cycles, respectively. Differences between both groups did not reach the level of significance. CONCLUSIONS In this randomized, comparative study, a sequentially combined oral HRT regimen consisting of oestradiol valerate (2 mg daily on days 1-21) and cyproterone acetate (1 mg daily on days 12-21), induced a lipid pattern and probably also a change in Lp(a) levels, which is generally viewed to be more beneficial with regard to the prevention of cardiovascular disease than the lipid pattern induced by a sequentially combined regimen of transdermal 17 beta-oestradiol (50 micrograms twice weekly during three weeks) and oral dydrogesterone (20 mg daily on days 12-21).