Summary. Background: Some data suggest that biological ‘resistance’ to aspirin or clopidogrel may influence clinical outcome. Objective: The aim of this study was to evaluate the relationship between aspirin and clopidogrel responsiveness in healthy subjects. Methods: Ninety-six healthy subjects were randomly assigned to receive a 1-week course of aspirin 100 mg day−1 followed by a 1-week course of clopidogrel (300 mg on day 1, then 75 mg day−1), or the reverse sequence, separated by a 2-week wash-out period. The drug effects were assessed by means of serum TxB2 assay, platelet aggregation tests, and the PFA -100® and Ultegra RPFA -Verify Now® methods. Results: Only one subject had true aspirin resistance, defined as a serum TxB2 level > 80 pg μL−1 at the end of aspirin administration and confirmed by platelet incubation with aspirin. PFA-100® values were normal in 29% of the subjects after aspirin intake, despite a drastic reduction in TxB2 production; these subjects were considered to have aspirin pseudo-resistance. Clopidogrel responsiveness was not related to aspirin pseudo-resistance. Selected polymorphisms of platelet receptor genes were not associated with either aspirin or clopidogrel responsiveness. Conclusions: In healthy subjects, true aspirin resistance is rare and aspirin pseudo-resistance is not related to clopidogrel responsiveness.