Postprocedural anticoagulation (AC) after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) may be administered for a number of specific therapeutic indications (e.g. atrial fibrillation or left ventricular thrombus). However, the safety and effectiveness of such post-PCI AC for specific indications are not well defined. Thus, we sought to study outcomes after postprocedural AC for specific indications in patients undergoing primary PCI for STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial. Patients who underwent primary PCI for STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial were grouped according to whether they received specific indication AC. Adverse outcomes were assessed using propensity-adjusted multivariate analyses. After excluding patients who received post-PCI AC solely for routine prophylaxis, 410 patients (16.6%) received postprocedural AC for specific indications and 2,063 patients (83.4%) received no post-PCI AC. After propensity adjustment, use of postprocedural AC for specific indications was associated with higher rates of cardiac mortality, reinfarction, stent thrombosis, and major bleeding at 30 days compared with patients who received no AC post-PCI. In conclusion, in this large prospective study, use of postprocedural AC for specific indications after primary PCI for STEMI was independently associated with early rates of adverse ischemic and hemorrhagic outcomes. Post-PCI AC for specific indications was also associated with worse outcomes from 30 days to 3 years. Further studies are warranted to determine the optimal use of postprocedural AC after primary PCI in STEMI.