Objectives: We sought to determine whether a 600-mg loading dose of clopidogrel reduces myocardial infarct size compared with a 300-mg using contrast-enhanced magnetic resonance imaging (MRI) in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Background: Recent data suggest that compared with 300-mg, a 600-mg loading dose of clopidogrel results in a higher and more rapid antiplatelet effect. Methods In 198 patients undergoing primary PCI for STEMI, MRI was performed a median of 7 days after the index event. The primary end point was myocardial infarct size as assessed by MRI. Results: Baseline characteristics were not significantly different between the 600-mg clopidogrel loading group (n=117) and the 300-mg group (n=81). The median infarct size was significantly smaller in the 600-mg group than in the 300-mg group (17.3% [8.9-26.2] versus 21.7% [12.9-30.0], p=0.03). Patients in the 600-mg group also had a significantly lower extent of microvascular obstruction and infarct transmurality than did those in the 300-mg group (0.9% [0-2.2] versus 1.5% [0-3.9], p=0.049 and 74.5% [61.7-83.9] versus 78.3% [68.9-86.7], p=0.04, respectively). After multivariate analysis, anterior infarction (OR 1.98, 95% CI 1.07-3.67, p=0.03) and angiographic no-reflow (OR 3.00, 95% CI 1.05-8.52, p=0.04) were independently predictive of a large infarct (infarct size>median 18.5%). A 600-mg clopidogrel loading dose showed a significant protective effect (OR 0.53, 95% CI 0.29-0.98, p=0.04). Conclusions: In patients undergoing primary PCI for STEMI, a 600-mg loading dose of clopidogrel reduced myocardial infarct size measured by MRI compared with a 300-mg loading dose.