Thrombophilia predisposes to venous thromboembolism (VTE) because of acquired or hereditary factors. Among them, it has been suggested that gene mutations of the factor V Leiden (FVL) or prothrombin G20210A mutation (PGM) might reduce the risk of bleeding, but little data exist for patients treated using anticoagulants. To assess whether thrombophilia is protective against bleeding. This multicentre, multinational, prospective cohort study evaluated adults receiving long-term anticoagulants after a VTE event. We analyzed the incidence of major bleeding as the primary outcome, according to the genotype for FVL and PGM (wild-type and heterozygous/homozygous carriers). Of 2260 patients with genotype testing, during a median follow-up of 3 years, 106 patients experienced a major bleeding event (17 intracranial and 7 fatal). Among 439 carriers of FVL, 19 experienced major bleeding and there were no differences between any mutation vs wild-type (hazard ratio HR, 0.89 0.53-1.49; p = .66). The comparison of major bleeding events between the 158 patients with any-PGM mutation (heterozygous or homozygous) vs wild-type also showed a nonstatistically significant difference with HR of 0.53 (0.19-1.43), p = .21. However, multivariate analysis demonstrated that major bleeds or clinically relevant nonmajor bleeding were statistically less likely for patients with either FVL and/or PGM compared with patients with both wild-type factor V and prothrombin genes (HR, 0.73; 95% CI = 0.55-0.97; p = .03). This study demonstrates that thrombophilia, defined as the presence of either FVL or the prothrombin G20210A mutation, is related with a lower rate of major/clinically relevant nonmajor bleeding while on anticoagulants in the extended treatment for VTE. •Thrombophilia is a status predisposing to venous thromboembolism, but it is unclear whether it is a protective factor against bleeding in patients on long treatment with anticoagulants for venous thrombosis.•We conducted a multicentre, multinational, prospective cohort study to evaluate the association between bleeding and factor V Leiden and prothrombin G20210A mutation.•During a median follow-up of 3 years, there was a nonstatistically significant difference between factor V Leiden or prothrombin G20210A mutation compared with wild-type.•Multivariate analysis has shown fewer bleeding events (major or clinically relevant nonmajor bleeding) for patients with factor V Leiden and/or prothrombin G20210A mutation vs both wild-type factor V and prothrombin genes.