OBJECTIVE: To determine the effect of continuous estradiol valerate 2 mg and norethisterone 0.7 mg daily as hormone replacement on lipid profiles, coagulation factors, haematology and biochemistry over 3 years. METHODS: An open label trial with 107-133 postmenopausal women assessed pre-treatment and at annual visits with extensive lipid and coagulation profiles, and observation of circulatory adverse events. Standard haematology and biochemical profiles were also analysed. Results were compared at point of entry and at 36 months. RESULTS: Total cholesterol (TC) and HDL and LDL fractions fell significantly (P=0.0001) and there was a significant decline in favourable ratios as well as a rise in VLDL mass (P=0.0001). Lipoprotein (a) (Lp(a)) decreased significantly (P=0.0053). Fibrinogen, free protein, prothrombin time and thrombin increased (P=0.0001) while platelets and KPTT were unchanged. Protein C, antithrombin III and total protein S decreased (P=0.0001) and there was a rise in the frequency of lupus anticoagulant positivity. Significant but small changes were seen in haematology and biochemical parameters although this did not raise safety issues and their clinical significance was uncertain. CONCLUSION: The direction of lipid and coagulation factors move in competing ways, emphasising the complexity of metabolic change and making interpretation of outcome for venous and arterial thrombosis or atherosclerosis difficult to predict. Eight patients developed thromboembolic or ischaemic events over the 3 year period of this study but these patients had lipid changes normally considered beneficial to cardiovascular disease and coagulation changes not thought to be associated with thromboembolism. Decrease in lipoprotein 'a' levels might be an indicator of long-term decreases in atherosclerotic events.