The antidepressant drug tianeptine increased rat plasma 5-hydroxyindoleacetic (5-HIAA) concentrations after single and repeated treatment for 14 days. This effect was not due to an increase in 5-hydroxytryptamine (5-HT) synthesis, as measured by the accumulation of 5-hydroxytryptophan in plasma and brain. A concurrent decrease in platelet-free plasma 5-HT concentrations occurred after subchronic treatment. Tianeptine attenuated the large increase in 5-HT concentrations in platelet-free plasma elicited by the specific 5-HT uptake inhibitors citalopram and paroxetine. These data are compatible with the reported 5-HT uptake-enhancing activity of this antidepressant drug.