Patients who have undergone orthopaedic surgery represent a high-risk group for venous thromboembolism (VTE). Despite the routine prophylactic use of antithrombotic agents, patients still experience thrombotic events that can result in mortality and acute morbidity and, in significant numbers of patients, may lead to long-term consequences such as the post-thrombotic syndrome. Increasingly, initial VTE events occur after hospital discharge since the length of stay in hospital after major orthopaedic surgery has decreased in many countries. There is a need for further improvement in the prevention of VTE. As well as undergoing extensive safety and efficacy studies for registration purposes, new prophylactic strategies need to be evaluated from a pharmacoeconomic perspective to help guide their introduction into routine clinical practice. Over the past 15 years a number of pharmacoeconomic evaluation studies of VTE prophylaxis have been carried out in orthopaedic patients, most of which evaluated short-term clinical endpoints. During the same period, improvements in our understanding of the natural history of VTE as well as the emergence of new treatments have led to changes in the management of patients with, or at risk of, VTE. The aim of this paper was to address how best to conduct pharmacoeconomic analyses of new antithrombotic agents in light of changes in practice patterns for orthopaedic patients and greater understanding of the disease process. We put forward recommendations for relevant outcome measures, timeframes, endpoints and epidemiologic data sources. We also suggest a structure for a pharmacoeconomic model. In this model, the outcomes and costs of VTE-related care during both the acute and chronic phases of the disease are incorporated. Symptomatic deep vein thrombosis and pulmonary embolism, recurrent VTE, post-thrombotic syndrome, major hemorrhage and all-cause death are included. We also recommend that the relevance of quality-adjusted survival is investigated, and that economic appraisals are presented in both cost-consequence and budget-impact approaches. These recommendations are based on extensive examination of recent advances in the management of VTE combined with a greater understanding of its natural history.