AIMS Pre-treatment with clopidogrel results in a reduction of ischaemic events in non-ST-elevation acute coronary syndromes. Data on upstream clopidogrel in the setting of primary percutaneous coronary intervention (PCI) are limited. The aim of this study was to investigate whether clopidogrel loading before arrival at the PCI centre may result in an improved outcome of primary PCI for ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS In a multicentre registry of acute PCI, 5955 patients undergoing primary PCI in Austria between January 2005 and December 2009 were prospectively enrolled. The patients consisted of two groups, a clopidogrel pre-treatment group (n = 1635 patients) receiving clopidogrel before arrival at the PCI centre and a peri-interventional clopidogrel group (n = 4320 patients) receiving clopidogrel at a later stage. Multiple logistic regression analysis including major confounding factors stratified by the participating centres was applied to investigate the effect of pre-treatment with clopidogrel on the in-hospital mortality. Additionally, two subgroups, with or without the use of GP IIb/IIIa antagonist therapy in the catheterization laboratory, were analysed. On univariate analysis, clopidogrel pre-treatment was associated with a reduced in-hospital mortality (3.4 vs. 6.1%, P< 0.01) after primary PCI. On multivariate analysis, clopidogrel pre-treatment remained an independent predictor of in-hospital mortality [odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.35-0.99; P =0.048], especially in patients receiving additional GP IIb/IIIa antagonist therapy in the catheterization laboratory (OR = 0.40, 95% CI 0.19-0.83; P =0.01). CONCLUSION Clopidogrel pre-treatment before arrival at the PCI centre is associated with reduced mortality in a real world setting of primary PCI. These results strongly support the recommendation of clopidogrel treatment 'as soon as possible' in patients with STEMI undergoing pimary PCI.