Venous thromboembolism (VTE) is the cause of significant morbidity and mortality and may lead to other complications, including recurrent VTE and long-term postthrombotic syndrome. Venous thromboembolism represents a huge health economic burden of nearly 500 million dollars/year in the United States. Without adequate prophylaxis, patients undergoing major orthopedic surgery are at high risk of developing VTE. Prophylaxis with either unfractionated heparin or warfarin not only substantially reduces the risk of VTE after orthopedic surgery, but also is more cost-effective than no prophylaxis. Low-molecular-weight heparins (LMWHs) have been shown to be superior to unfractionated heparin or warfarin, and despite the fact that they are more expensive, they are cost-effective. Large-scale clinical trials have shown that fondaparinux further reduces the likelihood of VTE complications after major orthopedic surgery. A review of the pharmacoeconomic evaluations of fondaparinux leads to the conclusion that fondaparinux is a cost-effective alternative to LMWHs in VTE prophylaxis.