On the basis of biologic studies of platelet reactivity, the recent American College of Cardiology and American Heart Association guidelines recommend a 600-mg loading dose (LD) of clopidogrel in patients who undergo percutaneous coronary intervention (PCI). There is, however, a lack of studies addressing the clinical impact of such a clopidogrel LD. The aim of this study was to compare the clinical efficacy and safety of a 600-mg LD of clopidogrel with that of a 300-mg LD in an unselected cohort of patients who underwent PCI. A cohort of 4,105 unselected patients who underwent PCI were included in the study and divided according to the LD used: the high-LD group (600 mg) included 3,146 patients, and the low-LD group (300 mg) included 959. The primary end point was the rate of major adverse cardiovascular events (MACEs) at 1 month. Patients in the low-LD group more often had diabetes mellitus and histories of myocardial infarction (36.8% vs 31.9%, p = 0.01). Left ventricular ejection fractions were similar (0.49 ± 0.14 vs 0.48 ± 0.14, p = 0.25). Angiographic and procedural characteristics were identical between the 2 groups. Patients in the high-LD group had fewer MACEs after 1 month (2.9% vs 5.2%, p <0.001). In multivariate analysis, an LD of 600 mg was significantly associated with MACEs at 1-month follow-up, with an odds ratio of 0.62 (95% confidence interval 0.41 to 0.95, p = 0.03). In conclusion, a 600-mg LD was associated with a significant decrease in the rate of post-PCI MACEs at 1 month, without any in-hospital increase in bleeding complications. The results of this study therefore support the current guidelines of a 600-mg LD of clopidogrel in patients who undergo PCI.