Background—: Concerns persist regarding the risk of stent thrombosis in the setting of primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Methods and Results—: The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial included 3602 patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention who were randomized to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) (n=1802) versus bivalirudin monotherapy (n=1800). Stents were implanted in 3202 patients, including 2261 who received drug-eluting stents and 861 who received only bare metal stents. Definite or probable stent thrombosis within 2 years occurred in 137 patients (4.4%), including 28 acute events (0.9%), 49 subacute events (1.6%), 32 late events (1.0%), and 33 very late events (1.1%). The 2-year cumulative rates of stent thrombosis were 4.4% with both drug-eluting stents and bare metal stents ( P =0.98) and 4.3% versus 4.6% in patients randomized to bivalirudin monotherapy versus heparin plus a GPI, respectively ( P =0.73). Acute stent thrombosis occurred more frequently in patients assigned to bivalirudin compared with heparin plus a GPI (1.4% versus 0.3%; P <0.001), whereas stent thrombosis after 24 hours occurred less frequently in patients with bivalirudin compared with heparin plus a GPI (2.8% versus 4.4%; P =0.02). Prerandomization heparin and a 600-mg clopidogrel loading dose were independent predictors of reduced acute and subacute stent thrombosis, respectively. Conclusions—: Stent thrombosis is not uncommon within the first 2 years after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction, and occurs with similar frequency in patients receiving drug-eluting stents versus bare metal stents and bivalirudin alone versus heparin plus a GPI. Optimizing adjunct pharmacology including early antithrombin therapy preloading with a potent antiplatelet therapy may further reduce stent thrombosis in ST-segment elevation myocardial infarction. Clinical Trial Registration:—: http://www.clinicaltrials.gov . Unique identifier: NCT00433966.