Background: Administration of a 300-mg clopidogrel loading dose is beneficial in situations requiring rapid platelet inhibition. Whether higher loading dose can provide further benefits remains still unclear. The aim of the present study was to evaluate the short-term and long-term efficacy and safety of a 600-mg loading dose of clopidogrel in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Methods: 565 patients with STEMI were enrolled in a nationwide prospective Korea Acute Myocardial Infarction Registry. 300-mg (n=324) or 600-mg (n=241) loading dose of clopidogrel were administered before PCI. Complications, in-hospital mortality, 1-month, 6-month and 12-month major adverse cardiac events (MACE) were evaluated. Results: The angiographic chatacteristics such as mean door-to-balloon time, success rate of primary PCI, post-PCI TIMI grade 3 flow and clinical chacteristics such as hypertension, diabetes were not different between the two groups. There was no significant difference in the incidences of complications including bleeding (17.6 vs 16.6%], in-hospital mortality (1.9) vs 0.8%). During the 1-month follow-up, 9 cardiac death (2.8%) occurred in the 300-mg loading group versus 2 (0.8%) in the 600-mg loading group (p=0.09). There was no significant difference in the incidences of all-cause-mortality, stent thrombosis, and target vessel revascularization during 6-month and 12-month follow-up. Conclusions: A 600-mg loading dose of clopidogrel did not reduce the MACE including cardiac death after PCI and appears to be safe in patients with STEMI.