Venous thromboembolism is a major health problem. In about 20% of cases, the initial clinical manifestation of venous thromboembolism is sudden death due to pulmonary embolism. Consequently, appropriate prophylaxis is critical in order to improve survival. Because patients with recent surgery have a 22-fold increased risk of postoperative venous thromboembolism, a large research effort has been directed toward identifying the safest and most effective prophylaxis after surgery, especially after total hip or knee replacement. While low-molecular-weight heparin is the most effective prophylaxis currently available, from 15% to 30% of hip or knee replacement patients still develop deep vein thrombosis by the time of hospital discharge, and another 25% develop new deep vein thrombosis by 3 weeks after discharge. Extended out-of-hospital low-molecular-weight heparin prophylaxis can safely reduce the prevalence of deep vein thrombosis by about 50%. However, essentially all of these thrombi are small, asymptomatic, and resolve without serious clinical sequelae. Based on one clinical trial, out-of-hospital low-molecular-weight heparin prophylaxis could reduce the incidence of symptomatic venous thromboembolism or all-cause death after discharge by a maximum of 2.2%. At current drug costs, universal out-of-hospital low-molecular-weight heparin prophylaxis is unlikely to be cost-effective. For most patients, 7 to 10 days of low-molecular-weight heparin prophylaxis is adequate. Future research should be directed at identifying patients at risk for out-of-hospital venous thromboembolism, and targeting extended prophylaxis to those at highest risk.