Cancer has been shown to be an independent risk factor for the development of venous thromboembolism (VTE; deep vein thrombosis and pulmonary embolism). Thromboprophylaxis reduces the incidence of VTE in patients with cancer; however, active cancer places patients at high risk for recurrent VTE, necessitating extended prophylactic regimens. Extended prophylaxis in patients with cancer can be problematic because of increased risk for bleeding. Oral anticoagulants, such as warfarin, have been the standard of care for extended prophylaxis, but maintaining a clinically effective level of anticoagulation can be difficult because of a wide range of drug interactions, a narrow therapeutic window, and an increased risk of bleeding complications, particularly in patients with cancer. Recent evidence indicates that long-term prophylaxis with low-molecular-weight heparins (LMWHs) is an effective and safe alternative to oral anticoagulation in patients with VTE and cancer, reducing the risk for recurrent VTE by up to 52%. LMWHs can also be seen as cost-effective for long-term prophylaxis, because higher drug acquisition costs are offset by the potential for reduced hospital stays, reduced need for coagulation monitoring, and fewer bleeding complications. Some studies suggest that LMWHs may also have direct antitumor effects and improve survival rates, most notably in patients with non-metastatic disease. Further clinical research is needed to evaluate the potential survival benefits of LMWH therapy in patients with cancer.