Clopidogrel is a prodrug that has to be converted to an active metabolite. CYP2C19 genotype is a key factor impacting the response to clopidogrel and the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. The prevalence of CYP2C19 loss-of-function alleles is much higher in East Asians including Japanese, than in people in Western countries. The American College of Cardiology Foundation (ACCF), American College of Gastroenterology (ACG) and American Heart Association (AHA) recommended in a 2010 conference that it is acceptable to use PPI with thienopyridines such as clopidogrel in patients at high risk of upper gastrointestinal bleeding. Several studies have indicated that concomitant use of clopidogrel and PPI is associated with reduced antiplatelet efficacy of clopidogrel, and increased adverse clinical outcomes after stent implantation in patients with acute coronary syndrome. However, several reports show that concomitant use of PPI and clopidogrel after stent implantation is not associated with an increased risk of cardiovascular events. We investigated whether CYP2C19 polymorphism or concomitant use of PPI and clopidogrel is associated with on-treatment platelet reactivity and clinical outcomes following stent implantation in patients with coronary artery disease. Our results indicated that the presence of CYP2C19 loss-of-function allele, but not the use of a PPI, was associated with an increased risk of cardiovascular outcomes. In conclusion, the use of a PPI should not be hesitated in patients with a high risk of gastrointestinal bleeding or ulcer.