Venous thromboembolism, a condition that includes deep vein thrombosis and pulmonary embolism, is a significant medical problem that affects more than 1 million patients each year. In addition to the immense impact of venous thromboembolism on morbidity and mortality, the economic burden of the disease is considerable, costing the health care system in the United States more than $1.5 billion/year. The cost of managing an initial episode of deep vein thrombosis is estimated at $7712-10,804, and for an initial pulmonary embolism event $9566-16,644. Management of acute venous thromboembolism in patients with cancer costs more than $20,000. Although much of the costs of venous thromboembolism are associated with managing the acute event, there are also significant costs associated with its long-term complications such as recurrent venous thromboembolism, postthrombotic syndrome, and pulmonary hypertension. Data from numerous robust clinical trials have demonstrated that with appropriate prophylaxis, many of these venous thromboembolism events can be prevented in both surgical and medical patients. Even though the strong evidence supporting venous thromboembolism prophylaxis spans several decades, a number of large American and global registries have documented very poor use of appropriate venous thromboprophylaxis. Because of increasing regulatory requirements, hospitals nationwide are developing necessary documentation of appropriate venous thromboembolism prophylaxis programs for both surgical and medical patients. Hospitals and clinicians must have a firm understanding of not only the clinical impact but also the economic impact of failing to use appropriate prophylaxis and of the cost-effectiveness of different venous thromboprophylaxis methods.