OBJECTIVES: The annual incidence of venous thromboembolic (VTE) disease in Europe is 183 per 100,000. If preventative measures are not taken one in three surgical patients can experience a VTE. This study estimated the cost-effectiveness of novel oral anticoagulants in two primary prevention populations; post hip (THR) and post knee (TKR) replacement surgery. METHODS: For both TKR and THR populations, initial consequences (180 days) were modelled using a decision tree, followed by a Markov model for long term consequences. We evaluated cost-effectiveness of dabigatran, rivaroxaban and apixaban, compared with low molecular weight heparin (LMWH). Subjects that experienced a recurrent event were treated with apixaban and then received aspirin daily for the remainder of their lives. Model inputs differed between the two populations.  Relative treatment efficacy and safety inputs came from network meta-analyses; other model inputs were based on a variety of evidence sources. Discounted (3.5%) health and benefits (QALYs) over a lifetime were estimated. RESULTS: In the THR population rivaroxaban had the highest incremental net monetary benefit of £453 (£-485 to £1,312) versus LMWH at a willingness to pay at £20,000 per QALY. Dabigatran and apixaban had a negative incremental net monetary benefit; £-1,066 (£-12,127 to £3,191) and £-2,284 (£-11,017 to £2,085) respectively. The results of the TKR population followed a similar trend. Rivaroxaban had the highest incremental net monetary benefit of £16 (£-406 to £329) at a willingness to pay of £20,000 per QALY. Dabigatran and apixaban had an incremental net monetary benefit; £-320 (£-2,844 to £638) and £-686 (£-2,458 to £266) respectively.  CONCLUSIONS: Rivaroxaban had the highest net monetary benefit at a willingness to pay threshold of £20,000 for primary prevention (THR and TKR). However, there was substantial uncertainty around these results in both populations.