Deep-vein thrombosis and pulmonary embolism are important causes of morbidity and mortality among patients undergoing major surgery. Fondaparinux is a new antithrombotic agent for use in prophylaxis, and this study compared its cost and effect vs. enoxaparin as prophylactic treatment in patients undergoing total knee replacement, total hip replacement, or hip-fracture surgery in Sweden. The analyses were based on a simulation model. Swedish data on cost for deep-vein thrombosis and pulmonary embolism were obtained from a large sample of patients undergoing major orthopedic surgery. The relative risk reduction for treatment with fondaparinux was estimated from results of four recently published clinical trials. The base case analyses showed that fondaparinux was cost saving and more effective than enoxaparin after total knee replacement and hip-fracture surgery and had costs per prevented venous thromboembolism of about <euro>239 after total hip replacement. Fondaparinux is thus more cost-effective than enoxaparin as prophylactic treatment in patients undergoing major surgery in Sweden.