OBJECTIVES: Venous thromboembolism (VTE) causes significant impact on morbidity/mortality and economic burden to health systems. For preventing VTE in hip fracture/arthroplasty, the American College of Chest Physicians Practice Guidelines recommends the use of antithrombotic agents, such as fondaparinux and low-molecular weight heparin (LMWH). We present a cost-effectiveness analysis of fondaparinux versus enoxaparin for the prevention of VTE in hip surgery in Brazil. METHODS: A decision model was developed with a 180-day post-surgery horizon for the comparison of fondaparinux versus enoxaparin, both administered during hospitalization (average eight days) for the prophylaxis of VTE in hip surgery. Thromboembolic event and major bleeding probabilities were derived from three major published randomized clinical trials comparing fondaparinux and enoxaparin (N>6,000). Costs were calculated using microcosting technique in search for hip surgery and thrombotic/hemorrhagic complications reimbursed from the public Brazilian Unified Health System Database (DATASUS) in June 2012. Drug prices for antithrombotic prophylaxis were extracted from the Health Prices Database (BPS) in 2012 (1BRZ=0.52USD). RESULTS: VTE was observed in 5.9% versus 11.5% of patients with fondaparinux and enoxaparin, respectively (relative risk reduction = 48.8%). Major bleeding (leading to death, reoperation or in critical sites) were similar in both groups, although bleeding with index >2 were more frequent in fondaparinux (2.4% versus 1.7%). Cost-effectiveness data showed fondaparinux was dominant over enoxaparin (i.e., reduced mortality at lower costs). There was an increment of three deaths per 1,000 patients by using enoxaparin instead of fondaparinux. Fondaparinux reported cost savings of BRZ16.53 per patient treated. Influence analysis showed that the incremental deaths and costs of enoxaparin were largely related to the higher incidence of thrombotic complications. CONCLUSIONS: Fondaparinux was found to be a cost-effective option under the Brazilian Public Health System perspective for the prophylaxis of VTE, resulting in lower mortality incidence at a reduced budget impact.