Background: The benefit of a higher loading dose of clopidogrel, compared with the conventional 300 mg loading dose, before primary percutaneous coronary intervention (PCI) is currently unclear. Objective: In the present study we evaluated safety and efficacy of a 600 mg loading dose of clopidogrel in patients ST-elevation myocardial infarction (STEMI) who underwent primary PCI. Methods: A cohort of 755 patients with STEMI, enrolled in the nationwide prospective Korea Acute Myocardial infarction Registry between January 2007 and January 2008, who underwent primary PCI after a clopidogrel loading dose of 600 mg was compared with 755 propensity-matched patients with STEMI who received a 300 mg loading dose before primary PCI. Angiographic and clinical outcomes in-hospital and at 30 days were assessed. Results: The mean door-to-balloon time was 2.4짹5.1 and 2.6짹5.9 hours in the 600 mg and 300 mg groups, respectively (p=0.388). Initial patency of the infarct-related artery (pre-PCI TIMI grade 2/3) was significantly higher in the 600 mg group than in the 300 mg group: 54.4% vs. 45.6%, p=0.034). The rate of post-PCI TIMI grade 3 flow was also significantly higher in the 600 mg group independently of the use of glycoprotein IIb/IIa inhibitor (85.8% vs. 89.3%, p=0.042). Compared to the 600mg group, a significantly higher proportion of patients in the 300 mg group received bare-metal stents (13.7% vs. 6.1%, p<0.0005) and required prolonged anticoagulation during hospitalization (low molecular weight heparin: 37.2% vs. 30.9%, 0.009; unfractionated heparin: 70.2% vs.58.5%, <0.0005). The length of hospital stay was significantly longer in the 300 mg group (7.1짹6.7 vs. 6.2짹5.7 days, 0.006). However, the incidence of in-hospital and 30-day ischemic events (bleeding complications, death, MI, or stent thrombosis) was similar between the two groups. Conclusion: Compared to the conventional 300 mg loading dose, the 600 mg loading dose of clopidogrel before primary PCI improved pre- and post-PCI patency and reduced the need for prolonged anticoagulation and hospital stay without increasing the risk of serious bleeding complications.