Background: Fondaparinux has been shown to reduce the risk of major bleeding and 30-day mortality compared with enoxaparin, in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). However, its cost effectiveness is not well known. Objective: To evaluate the effectiveness and economic attractiveness of fondaparinux relative to enoxaparin in patients with NSTE-ACS treated with triple antiplatelet therapy and early (non-urgent) invasive strategy. Methods: The decision model compares two alternative strategies: subcutaneous (SC) enoxaparin (1 mg/kg 12 hourly) versus SC fondaparinux (2.5 mg/day) in NSTE-ACS patients pre-treated with triple antiplatelet therapy and early revascularization. Cost-effectiveness and cost-utility analyses were performed from a healthcare perspective, based on a Markov model with a time horizon of the patient lifespan. Univariate sensitivity analysis and probabilistic (Monte Carlo) microsimulation analysis were performed. Results: In the base-case analysis (65 years, Thrombolysis In Myocardial Infarction [TIMI] score 4), the use of fondaparinux was associated with a significant reduction in major bleeding, a slight reduction in adverse cardiac events, and minor improvements in survival and QALYs, together with a small reduction in costs. The dominance of fondaparinux over enoxaparin remained unchanged in the univariate sensitivity analyses. According to Monte Carlo simulation, fondaparinux was cost saving in 99.9% of cases. Conclusion: Compared with enoxaparin, the use of fondaparinux in patients with NSTE-ACS managed with an early invasive strategy appears to be cost effective, even in patients with a low risk of bleeding.