OBJECTIVE: To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism. DESIGN: Population based case-control study. SETTING: Population enrolled in the General Practice Research Database, United Kingdom. SUBJECTS: A cohort of 347,253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10,000 controls were randomly selected from the source cohort. MAIN OUTCOME MEASURES: Adjusted relative risks estimated from unconditional logistic regression. RESULTS: The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10,000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10,000 women per year. CONCLUSIONS: Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.