INTRODUCTION: The first aim of this study is to evaluate the biological effect of doubling the maintenance dose of clopidogrel in pre-defined clopidogrel "low responders", compared to the biological effect of the standard dose in "responders". The second aim is to test the influence of the CYP 2C19*2 allele on clopidogrel responsiveness. MATERIALS AND METHODS: The platelet reactivity index (PRI), based on the phosphorylation status of the vasodilatator phosphoprotein, was determined in 81 consecutive cardiovascular outpatients who had been taking clopidogrel 75 mg/day for at least 15 days (visit 1). Patients with PRI>or=50% ("low responders") were then given clopidogrel 150 mg/day. All the patients were again evaluated 15 days later (visit 2) and were genotyped for the CYP 2C19*2 allele. RESULTS: At visit 1, PRI values ranged from 12.6% to 80.4%. In "low responders" (n=45), the mean PRI fell from 62.0+/-6.7% to 49.4+/-11.3% (P<0.001) after 15 days of clopidogrel 150 mg/day, while no significant change was observed in the other patients ("responders"), who remained on the standard dose (mean PRI: 37.7+/-10.4% and 39.9+/-10.8%, P=0.22, in visit 1 and 2, respectively). The CYP 2C19*2 allele was not associated with clopidogrel responsiveness. CONCLUSIONS: Increasing the maintenance dose of clopidogrel from 75 to 150 mg/day for 15 days in "low responders" is associated with a relative 20%-increase in its biological effect, independently of the CYP2C19 genotype, but without reaching the levels observed in "responders". The CYP 2C19*2 allele is not associated with clopidogrel responsiveness in our population of cardiovascular outpatients.