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In patients with high-risk non-ST-elevation acute coronary syndromes (NSTE-ACS), an invasive management strategy has been found to be superior to a conservative strategy. In the real world, similar to 50% of patients treated with an invasive strategy require a percutaneous coronary intervention (PCI) procedure, whereas the remaining 40-50% are treated medically and a small proportion (<10%) undergo coronary artery bypass graft surgery. Therefore, anti-thrombotic drugs need to be both safe and effective when started early in a broad range of patients with ACS, regardless of ultimate revascularization status. Fondaparinux is the first selective inhibitor of factor Xa approved for use across the whole spectrum of patients with ACS. In patients with NSTE-ACS in the OASIS-5 study, upstream treatment with fondaparinux was found to have superior net clinical benefit compared with enoxaparin in patients undergoing PCI. Fondaparinux reduced death, myocardial infarction, stroke, or major bleeding by 22% compared with enoxaparin (P = 0.004). Even in those undergoing early PCI (i.e. within the first 24 h), there was a 24% relative risk reduction in favour of fondaparinux (P = 0.035). The main benefit was a large 54% reduction in major bleeding (P < 0.001), which was achieved with near identical rates of ischaemic events (6.3 vs. 6.2%). Catheter thrombus occurred with very tow incidence in both the fondaparinux and the enoxaparin groups and was virtually eliminated in both groups with adjunctive unfractionated heparin (UFH) administered in the catheterization laboratory just prior to PCI. In the fondaparinux group, the mean dose of UFH was about 50 U/kg. On the basis of these data and the overall results of the OASIS-5 trial, the experts of the American College of Cardiology/American Heart Association and of the European Society of Cardiology gave fondaparinux a class I recommendation for use in patients with NSTE-ACS undergoing invasive strategy. In practice, fondaparinux is easy to use (fixed dose of 2.5 mg once daily for all patients) and is associated with improved patient outcomes, including those patients managed with an invasive strategy.