Fondaparinux (Arixtra) is the first of a new class of antithrombotic compounds - Factor Xa inhibitors. This synthetic pentasaccharide acts by inhibiting Factor Xa selectively. Its efficacy and safety have been demonstrated in animal models of venous and arterial thromboses and bleeding risk. In humans, its pharmacokinetic profile after subcutaneous injection shows a rapid onset of antithrombotic activity and an elimination half-life that reliably allows once-daily dosing. As the inter-subject variability is limited, no laboratory monitoring of coagulation parameters is needed. The efficacy and safety of fondaparinux have been examined in several Phase II and III clinical trials. So far, the largest programme has involved approximately 9000 patients undergoing major orthopaedic surgery of the lower limbs. In the setting of short-term prophylaxis, the efficacy of fondaparinux for preventing venous thromboembolism was significantly superior to that of the low-molecular-weight heparin, enoxaparin (common reduction in risk: 50.6%; p < 0.001). The benefit of extended thromboprophylaxis with fondaparinux in hip fracture surgery patients was also demonstrated. Fondaparinux also showed benefit in the prevention of venous thromboembolism in other surgical and medical settings and in the treatment of patients with venous thromboembolism. Overall, fondaparinux therapy was as well-tolerated as currently available treatments. In conclusion, selective inhibition of Factor Xa is an effective antithrombotic strategy. Fondaparinux may substantially improve the prevention and treatment of thrombosis. Fondaparinux 2.5 mg once-daily s.c. has been approved for the prevention of venous thromboembolism after major orthopaedic surgery. Fondaparinux use in extended prophylaxis (4 weeks) after hip fracture surgery has also been recently approved.