OBJECTIVES To develop a cost-effectiveness analysis of dabigatran etexilate versus enoxaparin for the prevention of venous thromboembolism after total knee replacement, under the Brazilian public health care system perspective. METHODS A decision tree analysis was developed for the first 180 days, considering the occurrence of deep vein thrombosis (DVT), pulmonary embolism (PE) and all-cause mortality, followed by two Markov models, for post-thrombotic syndrome and thromboembolic pulmonary hypertension. Long term costs and outcomes associated with the prevention of venous thromboembolism in patients receiving dabigatran or enoxaparin were, therefore, projected. The cycle duration was 1 month and the corresponding transition probabilities were obtained from the RE-MODEL study. The outcomes were expressed as the incremental number of all thromboembolic events and deaths related to the surgical procedure and its acute and late complications. The analysis considered only direct medical costs. Unit costs for drugs and procedures were obtained from Kairos Magazine (ex-factory price) and the National Database of Ambulatory Costs (SIA/DATASUS), respectively. Costs and outcomes were discounted at an annual 5% discount rate. A budget impact analysis was developed, considering the estimated number of total knee arthroplasties in the Brazilian public health care system in 2009. Main parameters were evaluated in a sensitivity analysis. RESULTS After a literature review, the evidences showed similar effectiveness between both alternatives. Total costs associated with dabigatran and enoxaparin were BRL279 (US$199) and BRL451 (US$322), respectively. The prophylaxis cost reduction was BRL172 (US$123), in favor of dabigatran. In 2009, total annual costs estimated for dabigatran and enoxaparin were BRL1,113,412 (US$795,294) and BRL1,800,886 (US$1,286,347), respectively, with a negative budget impact of BRL687,474 (US$491,053). (2005 purchasing power parity index 1USD=1.4BRL) CONCLUSIONS Dabigatran showed to be as effective as enoxaparin and cost-saving for the prevention of venous thromboembolism after total knee replacement under the Brazilian public health care system perspective.