OBJECTIVES: To analyze and compare medium and long-term clinical and economic outcomes of fondaparinux and enoxaparin in the prevention of venous thromboembolism (VTE) after major orthopaedic surgery (MOS) in Spain. METHODS: A decision-analytic model was adapted to determine the incidence and cost consequences of VTE-related events (deep vein thrombosis -DVT, pulmonar embolism -PE, and post-thrombotic syndrome -PTS) and major bleedings due to their prophylaxis and treatment, in 2 hypothetic cohorts of 10,000 MOS patients each who had received either 8 injections of enoxaparin or 7 injections of fondaparinux. Clinical outcomes and their direct cost consequences for the National Health System were calculated for different time horizons (1 month, 3 months, 1 year, and 5 years after surgery). Clinical input data were retrieved from published clinical trials and epidemiological studies. Resource use in the prophylaxis and management of all events was determined by an international expert panel using the Delphi technique and was validated for Spain by a local VTE expert. Unit costs of the resources were extracted from local databases and were expressed in Euros of 2002. Costs were discounted at 3% per year. RESULTS: Five years after surgery mortality caused by PE was 46% less in the fondaparinux cohort, while mortality due to major bleedings following prophylaxis or treatment of VTE did not differ between cohorts. The accumulated number of cases of DVT, PE, and PTS were, respectively, 33%, 46%, and 26% less. Additional drug cost with fondaparinux amounted to €14,582 per life saved. From three months after surgery onwards the price differential was compensated by savings that resulted from the avoidance of VTE-related events. CONCLUSIONS: Prophylaxis with fondaparinux vs. enoxaparin considerably reduces the number of fatalities and other VTE-related events after MOS and leads to net savings for the National Health System in the medium and long term.