OBJECTIVES: Assess cost-effectiveness of rivaroxaban, an oral direct Factor Xa inhibitor, versus subcutaneous enoxaparin for prevention of venous thromboembolism (VTE) following total knee replacement (TKR) in the UK and Spain. METHODS: RECORD3, a large randomized controlled trial, compared VTE prophylaxis for 12 days with rivaroxaban versus 12 days enoxaparin following TKR. Rivaroxaban reduced total VTE (composite: any DVT, non-fatal PE, all-cause mortality) by 49% and symptomatic VTE by 66% versus enoxaparin. A cost–utility model (healthcare perspective) assessed the cost-effectiveness over five years following TKR of rivaroxaban versus enoxaparin in the UK and Spain, two large European countries with different approaches to post-surgical prophylaxis and patient management. The model was populated using RECORD3 data. Published epidemiological and clinical data estimated risks of VTE and post-thrombotic syndrome beyond the trial period. Costs were derived from published local sources and expressed in pounds (£) for the UK and euros (€) for Spain. Utilities were taken from a systematic literature review. Potential savings from oral administration were included in the UK analysis only, as in Spain, drug administration costs are included in hospitalisation charges. RESULTS: The model showed rivaroxaban produced improved health outcomes and cost savings versus enoxaparin in the UK and Spain (dominance). Improved health outcomes were similar across both countries, while rivaroxaban produced cost savings of £89.15 per patient in the UK and €144.93 in Spain. Savings were driven by reduced costs of treating symptomatic VTE and associated long term complications, as well as oral outpatient administration in the UK. In both countries, probabilistic sensitivity analyses showed rivaroxaban maintained dominance versus enoxaparin in more than 99% of cases. CONCLUSIONS: Rivaroxaban is cost-effective following TKR within the different healthcare systems of both these two major European countries.