Carriers of a double thrombophilic mutation (factor V Leiden and prothrombin G20210A) are at high risk of a recurrent venous thromboembolism (VTE), and may benefit from a longer course of secondary prophylaxis. We examined the costs and health benefits of screening for both the mutations, provided that double heterozygotes undergo 2 years of anticoagulation as compared to the standard 6 months. We thus pooled the available evidence and calculated that the OR for recurrence in double heterozygotes was 5.9 (95% CI 2.65-13.20). A Markov model tracked patients' health lifelong, and calculated that prolonged prophylaxis saved 26 quality-adjusted days of life and $410 per double heterozygote treated. Screening all the patients with venous thromboembolism thus provided one additional day of life at the cost of 13624 $/QALY (95% CI 12 965-22 889). Screening was not cost-effective in those cohorts with a low prevalence of the mutations, a high bleeding risk or in those where prophylaxis prevented <65% of recurrences. Screening for factor V Leiden and prothrombin G20210A, with prolonged prophylaxis of double carriers, is cost-effective in most patients with VTE.