Friede KA, Infeld MM, Tan RS, et al. - To clarify whether the observed gender disparities in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke could be explained by underlying differences in platelet reactivity as well as aspirin response, this study was undertaken wherein healthy volunteers (n = 378,208 women) as well as patients with coronary artery disease or coronary artery disease risk factors (n = 217,112 women) were administered aspirin for 4 weeks. Platelet reactivity in response to epinephrine, collagen, and ADP was measured at baseline, 3 hours following the first aspirin dose, and after 4 weeks of daily aspirin therapy. Inhibition of platelet aggregation to a greater degree in response to epinephrine and to a lesser degree with collagen was noted in women at 3 hours after the first oral aspirin dose. Overall, findings revealed agonist‐dependent gender disparities in platelet responses to aspirin. A paradoxical reduction of platelet inhibition in response to epinephrine and ADP was evident over time as a consequence of daily aspirin exposure, despite higher cyclooxygenase‐1 inhibition, in women but not in men.