Trials of the new antithrombotic agent fondaparinux sodium in patients undergoing orthopedic surgery are discussed. Phase II studies conducted in more than 900 hip-replacement and 400 knee-replacement patients demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism. Phase III trials evaluated the efficacy and safety of fondaparinux sodium 2.5 mg s.c. once daily starting six hours after surgery compared with enoxaparin for prevention of venous thromboembolism (VTE). Four multicenter, randomized, comparative, double-blind Phase III trials were conducted: two in total hip replacement patients (Ephesus and Pentathlon 2000), one in knee surgery patients (PentaMaks), and one in hip fracture surgery patients (Penthifra). All four studies followed the same design template, and the comparator was one of two regimens of enoxaparin approved for this indication. Enoxaparin sodium 30 mg s.c. every 12 hours starting postoperatively was used in Pentathlon 2000 and PentaMaks, and enoxaparin sodium 40 mg s.c. once daily starting preoperatively was used in Ephesus and Penthifra. The primary efficacy endpoint was the occurrence of VTE up to day 11, as determined by venography or confirmation of symptoms. The main safety outcome was occurrence of major bleeding. In total, 7344 patients were randomized and efficacy was evaluated in 5385 (73.3%). Risk of VTE was reduced by 50% in patients receiving fondaparinux compared with those receiving enoxaparin. Safety profiles for clinically relevant bleeding were similar between the two drugs. Fondaparinux sodium, a novel antithrombotic agent, is effective for the prevention of VTE, with a favorable safety profile, in patients undergoing major orthopedic surgery.