The combination of unfractionated heparin (UFH) plus glycoprotein IIb/IIIa inhibitors (GPIs) has been a frequently used anti-thrombotic treatment strategy for acute coronary syndrome patients, including those with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. However, the ischemic benefit of the UFH plus GPI combination came at the expense of high rates of bleeding complications and thrombocytopenia, both of which have been independently associated with increased mortality. By contrast, bivalirudin monotherapy compared with the combination of UFH plus GPI resulted in improved net clinical outcomes, based on similar ischemic protection with significant reductions in bleeding complications in randomized trials including patients with stable angina, those with unstable angina and those with non-ST-segment elevation myocardial infarction. More recently, the HORIZONS-AMI randomized, open-label, multicenter trial has compared the efficacy and safety of bivalirudin alone versus UFH plus a GPI in 3602 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Clinical results derived from this large study, including the final 3-year follow-up data, will be reviewed in the present clinical trial report.