Background: Numerous studies have shown that estrogen replacement therapy (ERT) is an effective treatment for vasomotor symptoms, insomnia and vaginal dryness. Beneficial effects have also been shown on lipid patterns and on the incidence of osteoporotic fractures. As ERT increases the risk of endometrial adenocarcinoma, combinations with various progestogens have been developed in order to protect the endometrium. However, the addition of progestogens tends to reduce the beneficial effects of estrogens on mood, cognition and lipid metabolism. The added progestogen often causes side effects such as irritability and depression. There is evidence that the effect on wellbeing varies between women and with the type of progestogen used. Women who prefer to avoid withdrawal bleedings can be given continuous combined hormone replacement therapy (HRT). Unfortunately, irregular bleedings are common at the beginning of treatment and reduces compliance. Recently, several studies have reported an increased risk of breast cancer and venous thrombosis, and therefore long-term treatment with HRT for women without climacteric symptoms is no longer recommended. The ongoing debate has, for the time being, resulted in a recommendation that improving quality of life (QoL) by treatment of climacteric symptoms should be the only indication for prescribing HRT. Aims and methods: The aims of the study were to investigate bleeding patterns, changes in wellbeing at onset and during long-term treatment, and lipid and lipoprotein profiles with two different types of continuous combined HRT. In addition, women starting, and women switching from mainly sequential HRT were compared. The design was a randomised, double-blind, one year, prospective, multicentre study including 249 healthy postmenopausal women who were given continuous daily oral treatment with either combined 0.625mg conjugated estrogen (CE) and 5mg medroxyprogesterone acetate (MPA) or combined 2mg 17β - estradiol (E2) and 1mg norethisterone acetate (NETA). Bleedings, if any, were recorded daily throughout the study. The main outcome measures (changes in wellbeing and climacteric symptoms) consisted of daily ratings of 12 items on a validated symptom scale. Serum concentrations of lipids and lipoproteins were measured at baseline and after one year of treatment. Results and conclusions: The majority of drop-outs were confined to the first three months, and the main reasons were bleedings and/or decreased wellbeing. Drop-outs were three times more common in the E2/NETA group. During the first month, 67% of the women reported irregular bleedings. The number of bleeding days decreased on both treatments during the first four months. Treatment with CE/MPA resulted in less irregular bleedings and a shorter time to amenorrhoea compared to E2/NETA. As expected, "starters" experienced more sweats than "switchers" at the onset of treatment, but both groups improved significantly. Side effects such as breast tenderness, swelling, depression and irritability appeared during the first treatment week in both groups. The side effects of HRT appeared much more quickly than the benefits and were more frequent in women with a history of premenstrual syndrome (PMS). Breast tenderness was more common in the E2/NETA group throughout the whole study period. Apart from that, there were no differences between the two treatment regimens as regards effects on well-being at the end of the study. Lipoprotein(a) levels, an important risk factor for cardiovascular disease, decreased in both treatment groups. Triglyceride levels increased in women treated with CE/MPA, and levels of total cholesterol, high density lipoprotein and low density lipoprotein fell in the E2/NETA group. In conclusion, treatment with E2/NETA caused more bleeding problems than treatment with CE/MPA. CE/MPA was better tolerated than E2/NETA at the beginning of the study, but among the women remaining in the study there was no difference in QoL between the two treatment groups. HRT counselling should take into account that a history of PMS increases the likelihood of side effects and that these may precede any beneficial effects. Both treatments produced beneficial effects on lipid and lipoprotein levels, and neither of the regimens was superior in this respect.