Selective serotonin reuptake inhibitors efficiently decrease intraplatelet concentrations of the platelet activator and potent vasoconstrictor serotonin within 2 weeks of treatment. As elevated plasma serotonin levels potentially lead to vascular adverse events, like vasoconstriction, it is of interest to examine whether selective serotonin reuptake inhibitors may acutely increase plasma serotonin levels. Twenty healthy male smoking volunteers received the selective serotonin reuptake inhibitors paroxetine 20 mg/d for 18 days in a double-blind, placebo-controlled, block-randomized, 2-way crossover study to characterize the acute effect of paroxetine on serotonin plasma levels and urinary excretion. Paroxetine decreased intraplatelet serotonin concentrations by a median of 16% after 24 hours and by -93% after 18 days (P < 0.001). After 24 hours, there was a slight transient rise in plasma serotonin concentration by 36%-which ranged within physiologic concentrations of the control period. Concomitantly, urinary serotonin excretion increased by 89% after 24 hours. In conclusion, initiation of paroxetine treatment does not increase plasma concentrations of the potent vasoconstrictor serotonin to a pathologically relevant extent.