In the absence of thromboprophylaxis, venous thromboembolism (VTE) affects about 50 to 80% of the patients after total hip replacement (THR), total knee replacement (TKR), or hip fracture surgery. Since stratification of patients in those who will become symptomatic and those who will not, is not possible, primary high risk thromboprophylaxis should be provided to all patients undergoing major orthopedic surgery of the lower extremity. Various non-pharmacologic and pharmacologic thromboprophylactic measures have been evaluated. With regard to pharmacologic thromboprophylaxis unfractionated heparin has now almost completely been replaced by low molecular weight heparin (LMWH) for VTE prophylaxis. The use of acetylsalicylic acid for thromboprophylaxis in patients undergoing major orthopedic surgery of the lower extremities is not recommended. The optimal beginning of LMWH thromboprophylaxis is either 2 hours preoperatively or 6 to 8 hours postoperatively. Extended thromboprophylaxis (beyond 7 to 10 days after surgery) is recommended for high-risk patients. New antithrombotics, such as fondaparinux or (xi)melagatran, significantly reduce the risk of asymptomatic but not of symptomatic VTE compared to LMWH. In the light of other potential side effects (e.g., an increased bleeding risk) and high costs the role of these new drugs in the prophylaxis of VTE in patients undergoing major orthopedic surgery of the lower extremities remains to be established.