BACKGROUND: Among patients undergoing elective total hip or knee replacement, prolonged prophylaxis with low-molecular-weight heparin significantly reduces the risk of symptomatic venous thromboembolism. Whether implementing routine prolonged prophylaxis is cost-effective remains uncertain. METHODS: We performed an economic modeling study to compare the costs and health outcomes of standard (12 days) with prolonged (42 days) enoxaparin prophylaxis against venous thromboembolism after elective total hip and knee replacement. The primary economic perspective was that of a societal healthcare payer, taking Belgium as a case country. We used cost-utility analysis, a form of cost effectiveness analysis in which costs are reported in monetary terms (euros) and health outcomes are converted into quality-adjusted life years (QALYs) gained, thereby incorporating a measure of quality of life (utility) into the health outcomes. Costs for diagnosis and treatment of proximal and distal deep vein thrombosis, pulmonary embolism, postphlebitic syndrome, and major bleeding were obtained from a Delphi panel (orthopaedic surgeons) and the official reimbursement rates (Federal Ministry of Health). QALYs for these health outcomes were based on utility scores as reported in the literature. The main outcome measure was the incremental cost-utility ratio, reported as the incremental cost per quality-adjusted life year gained (euros/QALY). The incremental cost-utility ratio refers to the amount of money needed to produce one additional QALY. We also performed sensitivity analyses on clinical and economic parameters to identify important model uncertainties. RESULTS: In the base-case analysis, incremental costs of prolonged prophylaxis amounted to 58 euros and 114 euros per patient, with an additional gain in QALY of 0.0083 and 0.0018 after total hip and knee replacement, respectively. Thus, a strategy of prolonged enoxaparin prophylaxis was associated with a cost-utility ratio of 6,964 euros/QALY and 64,907 euros/QALY after total hip and knee replacement, respectively. This tenfold difference in incremental cost-utility ratios between hip and knee replacement might have important practical implications. According to recent European guidelines, an intervention costing less than 20,000 euros per QALY is said to exhibit strong evidence for adoption, whereas one costing 20,000-100,000 euros exhibits moderate evidence for adoption. By current European guidelines, the cost of 6,964 euros and 64,907 euros per QALY gained would give strong evidence for adoption of prolonged enoxaparin prophylaxis among total hip replacement patients, but moderate evidence for adoption among total knee replacement patients. Sensitivity analyses using 20% changes from the base-case analysis showed this outcome to be robust. CONCLUSIONS: Our findings indicate that, among patients undergoing elective total hip or knee replacement, prolonged enoxaparin prophylaxis leads to increased health benefits at increased cost. Given the additional costs that healthcare decision makers in Europe are usually prepared to pay for a gain in utility, prolonged prophylaxis with enoxaparin is cost-effective after elective total hip replacement, and our data provide strong evidence for adoption of prolonged enoxaparin prophylaxis after elective total hip replacement.