OBJECTIVES: To conduct a cost-effectiveness analysis (societal perspective) comparing standard anticoagulation care to genetic testing of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) to guide short-term warfarin therapy among patients with venous thromboembolism (VTE). METHODS: A decision model evaluated use of genotype testing to guide initial dosing during 6-months of warfarin therapy among VTE patients. The clinical and economic outcomes were associated with four alternatives: 1) CYP2C9 and VKORC1 genotype; 2) CYP2C9 genotype; 3) VKORC1 genotype; and 4) no testing. All clinical probabilities were derived from current scientific literature. Direct –medical and -nonmedical costs, and indirect costs were estimated from published databases and literature. Effectiveness was measured in quality-adjusted life-years (QALYs) at a discounted rate of 3%. All costs were in 2007 U.S. dollars. RESULTS: In the base case analysis, the genotype-guided dosing strategies demonstrated better health outcomes. Assuming a baseline prevalence of CYP2C9 associated warfarin sensitivity of 36% and of VKORC1 sensitivity of 63%, the marginal cost-effectiveness of the combination of CYP2C9 and VKORC1 genotype-guided dosing exceeded $100,000/QALY compared with VKORC1 testing alone. However, compared with no testing, the cost-effectiveness of testing decreased to