Pharmacoeconomic analyses can be readily applied to the study of venous thromboembolism (VTE) in the orthopedic postsurgical setting. The cost of VTE to the health care system and a cost-effectiveness trial that utilized a factor Xa inhibitor for VTE prophylaxis are discussed. The rationale for preventing VTE can be justified by its high frequency, asymptomatic nature, and high morbidity and mortality that result from unprevented thromboemboli. However, the economic burden that results from VTE is indeed significant. More effective antithrombotic prophylaxis would reduce the occurrence of VTE, the incidence of complications, and subsequent costs. Previous pharmacoeconomic analyses underscore the financial burden VTE places on the health care system in terms of increased length of hospital stay, time spent in the intensive care unit, and mean total cost. Trial-based and effectiveness-based analyses were utilized to compare the cost-effectiveness of a 7-day regimen of fondaparinux (2.5 mg once daily) and enoxaparin (30 mg twice daily). In the trial-based analysis, fondaparinux was estimated to prevent 15.1 thromboembolic events per 1000 patients at three months compared with enoxaparin; fondaparinux produced cost savings per patient at 30 days, 3 months, and 5 years postdischarge. In the effectiveness analysis, fondaparinux was estimated to prevent 17.7 thromboembolic events per 1000 patients at 3 months compared with enoxaparin; fondaparinux produced cost savings per patient at discharge, 1 month, 3 months, and 5 years postdischarge. These analyses demonstrate fondaparinux to be cost-effective for the prophylaxis of VTE in the orthopedic postsurgical setting.