Epidemiologic studies have identified Factor V Leiden as the most common cause of heritable thrombophilia, a prothrombotic mutation associated with a 5 to 7-fold increase in the risk of venous thromboembolism (VTE). In pre-menopausal women, the use of oral contraceptives is associated with a 4-fold increase in VTE risk, and the joint effects of oral contraceptive use and Factor V Leiden carriership increase the VTE risk of by a factor of 35. Recently, the results of several observational studies and randomized clinical trials suggest that in post-menopausal women, the use of hormone replacement therapy is associated with a 3-fold increase in VTE risk. Whether post-menopausal women with prothrombotic mutations experience a similar 20-fold increase in risk when they take post-menopausal hormones remains unknown.