Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of noncarriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used.Key words: venous thromboembolism, thrombophilia, anticoagulation, factor V Leiden, prothrombin G20210A. ollowing the discovery of factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) in the first half of the 1990s, numerous case-control, cross-sectional, and family studies have provided the convincing evidence that heterozygosity for either mutation is associated with a significantly increased risk of venous thromboembolism (VTE).1-3 This risk is higher in homozygous carriers and in carriers of double heterozygosity. While it is widely acknowledged that these mutations confer an increased risk of thrombosis, it is controversial whether patients who are heterozygous carriers of either mutation and develop a thrombotic episode have an increased risk of recurrent events in comparison with non-carriers.1-3 As a consequence, it is still not known whether detection of these abnormalities, which are highly prevalent in western countries, has the potential to identify a subgroup of patients who might benefit from the adoption of individually adjusted prevention strategies following their first thrombotic episode.4,5 Available literature dealing with this issue includes both prospective and retrospective investigations. By definition, prospective studies are methodologically stronger, as they imply the formation of an appropriate inc...