The field of medicine has a >30-year experience of prophylactic anticoagulation treatment in surgical patients, especially those with joint replacement and hip fracture. Extensive research to find anticoagulation alternatives beyond the use of unfractionated heparin has resulted in the development of low-molecular-weight heparin and vitamin K antagonist for prophylaxis of venous thromboembolism (VTE). In this article, drug administration regimens, pharmacologic activity, major adverse events, and costs for anticoagulation treatment are reported through a literature review. Clinical trial results are reported to provide the relative risk reduction and clinical benefit considerations in the administration of these drugs. The results show that in the absence of prophylactic treatment, hospital-acquired VTE occurs in approximately 10% to 40% of medical or general surgical patients and 40% to 60% of major orthopedic surgical patients. Patients treated in a major clinical study with the pentasaccharide fondaparinux demonstrated a 12.5% incidence of VTE compared with 27.8% of patients treated with enoxaparin (P <0.001). Major bleeding occurred in 3.1% of fondaparinux patients versus 0.3% 2 groups in the incidence of bleeding leading to death, reoperation or occurrence in a critical organ. The most recent anticoagulant class of drugs, oral direct thrombin inhibitors dabigatran and rivaroxaban, demonstrate great promise owing to fixed dosages, rapid onset and offset of action, and a predictable anticoagulation effect without coagulation monitoring. Multiple clinical trials are demonstrating efficacy and safety in VTE prevention and treatment. VTE is the leading cause of death in hospitalized patients. Successful prevention of VTE and fatal pulmonary embolism remain a challenge in patients undergoing surgery for hip fracture or joint replacement. The value of appropriate prophylaxis must be emphasized in these patients. Effective anticoagulation with intermittent pneumatic compression remains an underutilized regimen despite studies showing a significant reduction in mortality and morbidity. The newer oral direct thrombin inhibitors show significant promise.