OBJECTIVES: This study estimated the cost-effectiveness of novel oral anticoagulants for (i) acute treatment and (ii) secondary prevention, of VTE from the perspective of the NHS. METHODS: Secondary prevention:A Markov model was developed to evaluate cost-effectiveness of aspirin, rivaroxaban, dabigatran, warfarin (INR 2-3), apixaban 2.5mg and apixaban 5mg, compared to “no pharmacotherapy”. Acute treatment: A decision tree model for short term outcomes, followed by the secondary prevention model for long-term consequences, was used to evaluate cost-effectiveness of dabigatran, rivaroxaban, apixaban and edoxaban, compared with warfarin (INR 2-3). All interventions were considered at the licensed dose(s). Efficacy and safety parameters were informed by network meta-analyses and longitudinal studies were used to parameterise the long term follow up. The models had a life time horizon with costs and QALYs discounted at 3.5%. RESULTS: All results are presented at a £20,000 willingness to pay per QALY threshold Acute treatment:Apixaban showed the highest expected QALYs (12.02) and was the most cost-effective intervention with an incremental net monetary benefit of £645 (£-1,274 to £2,100) compared to Warfarin. Rivaroxaban also had a positive incremental net benefit (£167); all other comparators had a negative incremental net monetary benefit compared with warfarin. Secondary prevention:Although aspirin has a higher risk of recurrent VTE compared to the anticoagulants it had the highest incremental net monetary benefit compared with warfarin; £596 (£-6,494 to £4,524). This was due to the low cost and risk of adverse events of aspirin. All other comparators had a negative incremental net monetary benefit compared with warfarin. CONCLUSIONS: For acute treatment, apixaban had the highest probability (57%) of being cost-effective at a willingness to pay threshold of £20,000 for acute treatment. Novel oral anticoagulants are unlikely to be cost-effective for long term use in secondary prevention.