Factor Xa inhibition is a selective mechanism used for anticoagulation therapy. Clinical trials of drugs designed to inhibit factor Xa for the prevention of venous thromboembolism (VTE) after major orthopedic surgery are discussed. Hemostasis is a balanced process of blood coagulation and clot dissolution. Factor Xa is located at a key point in the clotting cascade, since it bridges the extrinsic and intrinsic pathways of this process. Inhibition of factor Xa via antithrombin (AT) by fondaparinux has been studied extensively. Fondaparinux selectively binds to AT, producing rapid anticoagulation with an approximate 300-fold potentiation of the natural inhibitory activity of AT against factor Xa. The anticoagulant demonstrates a linear dose response and is eliminated renally. Comparative trials conducted in major hip and knee surgeries established the efficacy and safety of fondaparinux in this setting. Overall, fondaparinux significantly reduced the incidence of VTE by day 11 (6.8%) compared with enoxaparin (13.7%)--common odds reduction of 55.2%. No difference in the incidence of clinically relevant bleeding (e.g, major bleeding leading to death or reoperation, or occurring in a critical organ) was observed. An increase in the occurrence of major bleeding was observed when the first dose was administered prior to 6 hours after surgical closure, resulting in the recommendation that the first dose be given 6 to 8 hours postsurgically. With strict adherence to recommendations for its use, fondaparinux may be used safely in certain special populations. Results from these large controlled trials predict that this factor Xa inhibitor will receive the highest recommendation in subsequent evidence-based guidelines for the prevention of VTE following major hip and knee surgeries, including surgery for hip fracture repair.