Based on their proven efficacy and relative safety, either LMWH or warfarin is recommended for prophylaxis by the American College of Chest Physicians Consensus Conference in major orthopedic surgery. There is, however, room for improvement. Stimulated by this perceived clinical need, the relative efficacy and safety of a new anticoagulant, fondaparinux, has been compared with the LMWH, enoxaparin, in a number of randomized trials in total hip, total knee, and fractured hip surgery. Dr. Bauer reviews the pharmacology of fondaparinux, and Dr. Turpie describes the clinical development program in orthopedic surgery. Fondaparinux, a synthetic pentasaccharide with high affinity for its specific target, antithrombin, catalyzes the inhibition of factor Xa. Fondaparinux has excellent bioavailability, does not bind to plasma proteins or platelets, and has a half-life of 17 h, allowing once-daily dosing by subcutaneous injection. It does not crossreact with heparin-induced thrombocytopenia antibodies, and is cleared through a renal mechanism. Fondaparinux has a favorable efficacy-to-safety profile in experimental animal models.