OBJECTIVES: Venous thromboembolism (VTE) is a relevant  cause of morbidity and mortality in patients undergoing major orthopaedic surgery (MOS). Thromboprophylaxis  is recommended  in this setting and low-molecular-weight-heparins  (LMWHs) are  the anticoagulant agents most frequently used. Fondaparinux is an effective and safe alternative in this setting. Objective of our study was to investigate the cost-effectiveness of fondaparinux versus  enoxaparin from the perspective of the Italian National Health Service (NHS) in patients undergoing MOS. METHODS: A decision tree model was developed in order to compare fondaparinux with enoxaprin in extended thromboprophylaxis of patients undergoing MOS. Probabilities of symptomatic events were derived from the results of randomized controlled trials; use of resources in common clinical practice in Italy was evaluated by means of an “ad hoc” questionnaire administered to a panel of experts. Only direct cost of VTE (acute treatment of events and of complications) were included in the analysis.  Cost units were derived from current cost of drugs and from Italian National Healthcare tariffs for tests and medical visits in 2007 (in Euros). Incremental Cost-Effectiveness ratios were analysed at three time points: 30 days, one year, five years. RESULTS: After 30 days of extended prophylaxis fondaparinux was associated with a lower cost compared with enoxaparin, leading a saving of €48.83 per patient. At the end of the first year after MOS, the saving is increased to €72.13: rates of late PE and late DVT which are higher with enoxaparin, particularly for patient undergoing total hip replacement (which is the 34% of the population of the model), accounted for this difference. Overall, after 5 years the saving with fondaparinux is €74.36 per patient. Direct cost  of prophylaxis is higher with fondaparinux, but this is highly compensated by the different rates of early DVT, early PE and prophylaxis-related major bleeding. One-way sensitivity analysis showed that results were robust to the variation in unit costs for  VTE related care or in event rates for both treatments. CONCLUSIONS: The different rates of early and late DVT, PE and prophylaxis-related major bleeding overbalanced the lower cost of enoxaparin, in favour of fondaparinux. Our model suggests that fondaparinux is cost-saving when compared to enoxaparin for VTE prophylaxis in patients undergoing MOS in Italy.