In the setting of ST-segment elevation myocardial infarction (STEMI), patients at high risk of systemic emboli who undergo primary percutaneous coronary intervention (PCI) using stents might require triple antithrombotic therapy (a combination of aspirin, thienopyridine, and vitamin K antagonist [VKA]). The risks and benefits of such therapy in the setting of STEMI have been incompletely characterized. We, therefore, assessed the outcomes of patients who received triple therapy after primary PCI in the large-scale, contemporary Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial. Among the 3,320 patients triaged to primary PCI, 126 (3.8%) were prescribed triple therapy and 3,194 (96.2%) were prescribed dual antiplatelet therapy. The most frequent indications for VKA treatment were a severely reduced left ventricular ejection fraction with a large akinetic area, atrial fibrillation (23.8% each), and mural thrombus (23.0%). The assignment to triple therapy was associated with older age, female gender, rhythm disturbances, Killip class > 1 on admission, lower left ventricular ejection fraction, left anterior descending artery territory infarcts, and Final Thrombolysis In Myocardial Infarction flow grade < 3. Patients treated with triple versus dual therapy had comparable short- and long-term ischemic outcomes but had significantly increased rates of major bleeding during the index hospitalization (17.1% vs 6.5%, p < 0.0001), resulting in premature VKA discontinuation in 14.3% of those patients. In conclusion, in the setting of STEMI treated with primary PCI, the combination of aspirin, thienopyridine, and VKA results in an excess of bleeding complications and premature discontinuation of VKA. The risk of adding oral anticoagulation to patients admitted for STEMI should be carefully considered before choosing drug-eluting or bare metal stents.