OBJECTIVES Patients treated with total knee arthroplasty are at high risk for the development of venous thromboembolism postoperatively resulting in poor health outcomes and generating additional costs to the health care system. The purpose of this study was to estimate the cost-effectiveness of different thromboprophylactic agents to prevent VTE associated with knee surgery from an institutional perspective. METHODS A six-state stochastic Markov model was constructed to simulate health and economic outcomes during a time horizon of one year (1-week cycles). Effectiveness measures were prevention of events of deep vein thrombosis (DVT) and pulmonary thromboembolism(PE); and reduction of recurrent hospitalizations and deaths. Markov transition probabilities were obtained from a meta-analysis employing international published literature. Comparators employed were warfarin(5mg/day); dalteparin(2,500,5,000,7,500IU/day); enoxaparin (20,40,60mg/day); nadroparin(57,00IU/day); unfractionated heparin(UFH) plus warfarin(10,000,30,000,42,000IU/day+5mg/day); fondaparinux(2.5-7.5mg/day) and no prophylaxis intervention. Resource use and costs were collected from clinical records (n=7000) from Social Security Mexican Institute(IMSS) hospitals. Costs include outpatient and inpatient services, drug, procedures, etc. The model was calibrated according to international guidelines. Probabilistic sensitivity analyses were performed employing bootstrapping techniques and acceptability curves were constructed. RESULTS Incidence of PE and related deaths were significantly lower for patients treated with dalteparin(p<0.05). Regarding the prevention of PE events, dalteparin 2500, 5000 and 7000IU/day showed an ICER[CI95%] of US$1932.88[US$1,888.67-US$1977.11]; US$1800.87[US$1759.67-US$1842.07] and US$1718.52[US$1679.21-US$1757.84]; against warfarin(gold-standard), respectively. In addition, UFH yielded an ICER of US$23.35[US$22.82-US$23.89] and fondaparinux of US$1410.74[US$1378.47-US$1,443.02]. However, enoxaparin, nadroparin, and no prophylaxis alternatives were dominated. Second-order Monte Carlo sensitivity analyses demonstrated a trend that dalteparin would be more cost-effective than enoxaparin in a range of 50%-60%(p<0.05) in PE events avoided. CONCLUSIONS At IMSS, dalteparin compared to warfarin would be a cost-effective thromboprophylactic therapy to reduce risk of PE and DVT events associated with total knee arthroplasty and showed 75% less related deaths than enoxaparin. These results could be useful for future cost-containment policies.