We evaluated the effect and optimal dose of clopidogrel pretreatment in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention (PPCI). The study included 383 consecutive patients with ST-elevation myocardial infarction who had undergone PPCI and were prospectively followed up for a prespecified primary end point of recurrent acute coronary syndrome, stent thrombosis, congestive heart failure, and/or death at 30 days. Of these patients, 217 (57%) received clopidogrel loading before and 166 (43%) after PPCI. A similar number received low (300 mg) and high (600 mg) clopidogrel doses before and after PPCI. Clopidogrel loading before, compared with after, PPCI was associated with a lower incidence of the primary end point (21.7% vs 33.7%, p = 0.008). Clopidogrel pretreatment remained a significant predictor of the primary outcome after adjusting for potential confounders (odds ratio 0.54, 95% confidence interval 0.42 to 0.91). When patients were further stratified into 4 groups according to the timing and dosage of clopidogrel loading, the incidence of the primary outcome was 16% and 27% in those receiving 600 and 300 mg before and 28% and 39% in those receiving 600 and 300 mg after PPCI, respectively (p for trend <0.01). In conclusion, both the timing and the dosage of clopidogrel loading are important and affect the outcome in patients with ST-elevation myocardial infarction undergoing PPCI.