OBJECTIVES: To estimate the cost-effectiveness of extended-duration venous thromboembolism (VTE) prophylaxis with betrixaban compared to standard-duration VTE prophylaxis with enoxaparin or fondaparinux in hospitalised, nonsurgical patients with acute medical illness at risk of VTE in the United Kingdom (UK). METHODS: The cost-effectiveness analysis estimated the cost per quality-adjusted life-year (QALY) gained for betrixaban (35-42 days) compared to enoxaparin (6-14 days) or fondaparinux (7 days) from the UK National Health Service perspective over a lifetime horizon. For the first three-months, a decision tree structure estimated primary events and treatment complications (TCs) based on efficacy from the Phase 3 APEX study for betrixaban and enoxaparin. A network meta-analysis informed symptomatic DVT, pulmonary embolism and VTE-related death rates in fondaparinux patients compared to betrixaban for the decision tree, otherwise fondaparinux was assumed equivalent to enoxaparin. Primary events included VTE, myocardial infarction, ischemic stroke and death; all-cause or VTE-related. TCs included major bleeding, clinically relevant non-major bleeding and heparin induced thrombocytopenia. After three-months, patients entered a six-health state Markov model and were at risk of recurrent events and long term complications. Costs included treatment and management of primary events, TCs, recurrent events and complications. Published literature identified the risk of recurrent events and long term complications, EQ-5D utility data and costs. A 3.5% discount rate per annum was used. Uncertainty was explored through deterministic and probabilistic sensitivity analysis. RESULTS: Betrixaban dominated both enoxaparin and fondaparinux, leading to cost savings of £180 and £166 and increased QALYs of 0.021 and 0.020 per patient, respectively. Furthermore, betrixaban dominated enoxaparin and fondaparinux across all sensitivity analyses. CONCLUSIONS: Betrixaban improved QALYs and was less costly than enoxaparin or fondaparinux, and could therefore be considered a cost-effective regimen for hospitalised, nonsurgical patients with acute medical illness at risk of VTE, who require extended-duration VTE prophylaxis from hospitalisation through post-discharge.