Studies conducted in the first three decades after discovery of a link between venous thromboembolism and oral contraceptive users showed a relative risk of first thrombosis during oral contraceptive use of 2.9 (95% CI 0.5-17). In recent studies in which the sub-50 micrograms ethinyl estrodiol containing pills were investigated comparing current users with non-users, the RR is 3.8 for non-fatal deep VTE and 2.7 for superficial VTE, deep VTE and pulmonary embolism (PE) together and 2.1 for fatal VT and PE together. The association is attributed to the estrogenic component and not related to duration of pill use. The risk disappears once the pill has been stopped, and it is not elevated among past users. Smoking does not appear to be risk factor for VTE; obesity and varicose veins are, at the most, weak risk factors. Since a causal relationship between OC use and VTE is tempting, clues for unraveling the mechanism were sought in the hemostatic system. Studies of the coagulation system found changes in the activation of coagulation and fibrinolytic compartments, but within the normal range. An epidemiologic study showed that the risk of VTE among women using OCs is 30-fold increased by the presence of a mutation of factor V, called Factor V Leiden (5% prevalence in the Caucasian population). Selective screening for the mutated factor V should be limited to women with a personal or family history of VTE. Four epidemiologic studies showed a two-fold increase in risk of VTE with the use of OCs containing third-generation progestins (gestodene and desogestrel), relative to second-generations products (levonorgestrel). Biases cannot devaluate the conclusion that the increased risk of VTE in especially first-time and younger users of third-generation OCs is highly likely. The clinical consequence is therefore that second-generation OCs are the first choice in prescription to first-time users.