Aims: We conducted an cost-utility analysis to compare standard (in-hospital) with prolonged (out-of-hospital) enoxaparin prophylaxis after elective total hip and knee replacement. Methods: The perspective was that of a societal healthcare payer, taking Belgium as a case country. The main outcome measure was the incremental cost-utility ratio, reported as the incremental cost per quality-adjusted life year gained (Euro/QALY). 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 Ministery of Health). QALYs for these health states were based on utility scores as reported in the literature. Results: In the base-case analysis, incremental costs of prolonged prophylaxis amounted 58 Euro and 114 Euro 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 Euro/QALY and 64,907 Euro/QALY after total hip and knee replacement, respectively. Applying a societal willingness-to-pay threshold value of 20,000 Euro/QALY, prolonged enoxaparin prophylaxis is cost-effective after elective total hip replacement. Sensitivity analyses confirmed the general robustness of these findings. Conclusions: After elective total hip or knee replacement, prolonged enoxaparin prophylaxis leads to increased effectiveness at increased cost. Nevertheless, given the additional costs healthcare decision makers in Europe are usually prepared to pay for a gain in effectiveness, prolonged prophylaxis with enoxaparin is cost-effective after total hip replacement