OBJECTIVE To assess the effects on the postmenopausal endometrium of two doses of oral piperazine oestrone sulphate and interrupted norethisterone in comparison with a continuously combined regimen and placebo. METHODS A prospective randomised trial. METHODS Two hundred healthy postmenopausal women. METHODS Random assignment to two years of treatment with alternating three-day cycles of 1.5 mg piperazine oestrone sulphate and 1.5 mg piperazine oestrone sulphate + 0.7 mg norethisterone (highEP), or alternating three-day cycles of 0.75 mg piperazine oestrone sulphate and 0.75 mg piperazine oestrone sulphate + 0.35 mg norethisterone (lowEP), or 2 mg 17 beta-oestradiol continuously combined with 1 mg norethisterone acetate (E2+NETA), or placebo. METHODS Effect of treatment on endometrial histology, endometrial thickness, occurrence of uterine bleeding, endometrial oestrogen and progesterone receptor content, endometrial isocitrate dehydrogenase activity, and serum placental protein 14. RESULTS The incidence of bleeding declined with time. In the second treatment year, the women receiving lowEP reported on average 7.3 days of bleeding, highEP 16.7 days, and E2+NETA 11.2 days. Histological assessment of endometrial biopsies revealed an atrophic or slightly secretory endometrium. Serum placental protein 14 increased slightly, but was statistically highly significant, during treatment, but no cyclical variation was observed. Endometrial isocitrate dehydrogenase was low in all three hormone groups and the same low level of endometrial oestrogen receptor and progesterone receptor was found comparable to the level in the placebo group. CONCLUSIONS Histological and biochemical assessment of the endometrium showed that interrupted hormone replacement therapy induced the same pattern in endometrial parameters as continuous combined hormone replacement therapy.