BACKGROUND Serotonin is a platelet agonist and potent vasoconstrictor that has recently received attention concerning its potential role in acute coronary artery thrombosis. Selective serotonin-reuptake inhibitors, such as paroxetine, are widely used antidepressant agents. We sought to characterize the potential inhibitory effect of paroxetine on platelet function. METHODS Healthy male volunteers received 20 mg/d paroxetine for 2 weeks in a randomized, double-blind, placebo-controlled, two-way cross-over trial. RESULTS Paroxetine decreased intraplatelet serotonin concentrations by -83% (P < .01). This inhibited platelet plug formation as reflected by a 31% prolongation of closure time measured with the platelet function analyzer-100 (P < .05). Furthermore, paroxetine lowered expression of the platelet activation marker CD63 in response to two different concentrations of thrombin receptor-activating peptide (P < .01). Plasma concentrations of prothrombin fragment, von Willebrand factor antigen, and circulating P-selectin remained unchanged in either period, indicating that paroxetine does not increase activation of coagulation, endothelium, or platelets in vivo, underlining a favorable safety profile. CONCLUSIONS Paroxetine substantially decreases intraplatelet serotonin content and thereby reduces platelet plug formation under shear stress, and responsiveness to thrombin receptor activating peptide-induced platelet activation. Further studies will reveal whether these pharmacodynamic effects can be exploited for treatment of thrombotic artery disease.