Current guidelines discourage combined oral contraceptive (COC) use in women with hereditary thrombophilic defects. However, qualifying all hereditary thrombophilic defects as similarly strong risk factors might be questioned. Recent studies indicate the risk of venous thromboembolism (VTE) of a factor V Leiden mutation as considerably lower than a deficiency of protein C, protein S, or antithrombin. In a retrospective family cohort, the VTE risk during COC use and pregnancy (including postpartum) was assessed in 798 female relatives with or without a heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin G20210A mutation. Overall, absolute VTE risk in women with no, single, or combined defects was 0.13 (95% confidence interval 0.08-0.21), 0.35 (0.22-0.53), and 0.94 (0.47-1.67) per 100 person-years, while these were 0.19 (0.07-0.41), 0.49 (0.18-1.07), and 0.86 (0.10-3.11) during COC use, and 0.73 (0.30-1.51), 1.97 (0.94-3.63), and 7.65 (3.08-15.76) during pregnancy. COC use and pregnancy were independent risk factors for VTE, with highest risk during pregnancy postpartum, as demonstrated by adjusted hazard ratios of 16.0 (8.0-32.2) versus 2.2 (1.1-4.0) during COC use. Rather than strictly contraindicating COC use, we advocate that detailed counseling on all contraceptive options, including COCs, addressing the associated risks of both VTE and unintended pregnancy, enabling these women to make an informed choice.