The typical duration of hospitalization following major knee and hip surgeries may not provide adequate time for effective prophylaxis of venous thromboembolism (VTE) when inpatient therapy only is administered. Results from a clinical trial that extended the duration of VTE prophylaxis after hip fracture surgery are reviewed. The risk of VTE after major knee and hip arthroplasty has been demonstrated to extend into the outpatient period. Although extending the duration of VTE prophylaxis has been demonstrated to decrease the incidence of VTE following total hip replacement, no randomized, double-blinded assessment had demonstrated the effectiveness of this strategy following hip fracture surgery. A multicenter, randomized, placebo-controlled, double-blind trial was conducted to assess prolonged prophylaxis of VTE in patients undergoing surgery for fracture of the upper third of the femur. Patients received an initial 7 +/- 1 day open period of treatment with subcutaneous fondaparinux (2.5 mg once daily); 656 patients were subsequently randomized to receive a 21 +/- 2-day double-blind treatment period of either the same fondaparinux regimen or placebo. Fondaparinux treatment produced statistically significant reductions in the incidence of all VTE events (1.4% compared with placebo 35.0%); prolonged prophylaxis was associated with a 96% relative risk reduction for VTE (p < 0.001). Also, no differences were observed in the incidence of other major endpoints such as bleeding or death. These results indicate that extended prophylaxis with fondaparinux significantly reduces the risk of VTE without increasing the risk of major bleeding.