Elevated troponin after elective percutaneous coronary intervention (PCI) has been associated with a worse prognosis. Pretreatment with clopidogrel may be beneficial in patients undergoing PCI. Therefore, a prospective observational study was conducted to address the potential role of clopidogrel in reducing troponin release after elective PCI. TroponinT was measured 12 hours after elective PCI in 656 patients without elevated troponin before PCI. To assess the independent association between pre-treatment with clopidogrel and increased troponin, multivariate analyses were performed. Mean age of the 656 patients was 63.5 years (SD 10.2), 194 patients (30%) were female and 114 patients (17.4%) had diabetes. In 217 patients (33%) troponin was increased after PCI. Of the 330 patients who were not pre-treated with clopidogrel, 118 patients (34%) had increased troponin after the PCI compared to 99 patients (30%) of the 326 patients who were treated with clopidogrel longer than 24 hours before the procedure (p = 0.14). Stratified analyses showed that patients with older age (p = 0.03), previous PCI (p = 0.013), angina CCS 4 (p = 0.03) and multivessel disease (p = 0.04) had a significantly lower risk of troponin increase after pre-treatment with clopidogrel compared to patients without pre-treatment. After adjusting for differences in the other variables, patients who were pre-treated with clopidogrel had a significant lower risk of post-PCI increase of troponin T (odds ratio 0.69, 95% confidence interval 0.49-0.99). Pre-treatment with clopidogrel is associated with a significantly lower incidence of increased troponin after elective PCI. Combined with results of other studies, pre-treatment should be advised in patients waiting for elective PCI.