The combined use of antithrombotic agents, antiplatelet agents and invasive strategies in acute coronary syndrome without ST-segment elevation (ACSWSTE) reduces cardiovascular events. Fondaparinux has demonstrated equivalence to enoxaparin in reducing cardiovascular events, but with a lower rate of bleeding in patients using fondaparinux.Evaluate the cost-effectiveness of fondaparinux versus enoxaparin in patients with ACSWSTE in Brazil from the economic perspective of the Brazilian Unified Health System (SUS).A decision analytic model was constructed to calculate the costs and consequences of the compared treatments. The model parameters were obtained from the OASIS-5 study (N = 20,078 patients with ACSWSTE randomized to fondaparinux or enoxaparin). The target outcome consisted of cardiovascular events (i.e., death, myocardial infarction, refractory ischemia and major bleeding) on days 9, 30 and 180 after ACSWSTE. We evaluated all direct costs of treatment and ACSWSTE-related events. The year of the analysis was 2010 and the costs were described in reais (R$).On day 9, the cost of treatment per patient was R$ 2,768 for fondaparinux and R$ 2,852 for enoxaparin. Approximately 80% of total costs were associated with invasive treatments. The drug costs accounted for 10% of the total cost. The combined rates of cardiovascular events and major bleeding were 7.3% and 9.0% for fondaparinux and enoxaparin, respectively. Sensitivity analyses confirmed the initial results of the model.The use of fondaparinux for the treatment of patients with ACSWSTE is superior to that of enoxaparin in terms of prevention of further cardiovascular events at lower cost.