Increased residual platelet reactivity remains a burden for coronary artery disease (CAD) patients who received a coronary stent and do not respond sufficiently to treatment with acetylsalicylic acid and clopidogrel. We hypothesized that serotonin antagonism reduces high on-treatment platelet reactivity. Whole blood impedance aggregometry was performed with arachidonic acid (AA, 0.5 mM) and adenosine diphosphate (ADP, 6.5 µM) in addition to different concentrations of serotonin (1-100 µM) in whole blood from 42 CAD patients after coronary stent placement and 10 healthy subjects. Serotonin increased aggregation dose-dependently in CAD patients who responded to clopidogrel treatment: After activation with ADP, aggregation increased from 33.7 ± 1.3% to 40.9 ± 2.0% in the presence of 50 µM serotonin (p<0.05) and to 48.2 ± 2.0% with 100 µM serotonin (p<0.001). The platelet serotonin receptor antagonist ketanserin decreased ADP-induced aggregation significantly in clopidogrel low-responders (from 59.9 ± 3.1% to 37.4 ± 3.5, p<0.01), but not in clopidogrel responders. These results were confirmed with light transmission aggregometry in platelet-rich plasma in a subset of patients. Serotonin hence increased residual platelet reactivity in patients who respond to clopidogrel after coronary stent placement. In clopidogrel low-responders, serotonin receptor antagonism improved platelet inhibition, almost reaching responder levels. This may justify further investigation of triple antiplatelet therapy with anti-serotonergic agents.