Serotonin (5-HT) plays an important role as both a neurotransmitter and animmune modulator. The serotonin reuptake transporter (SERT) clears the extracellular space of 5-HT, which decreases the effects of 5-HT on target cells. This study demonstrated that the RAW264.7 macrophage cell line expresses SERT function, measured by assays of 3H-5HT uptake. The 5-HT uptake in RAW264.7 macrophages was more than 10-fold that of peritoneal macrophages, indicating that these cells are an excellent model for studying regulation of the SERT. Activation of macrophages with lipopolysaccharide (LPS) increased SERT activity in a time- and concentration-dependent manner and Western blots indicate that the increase in activity is partially due to LPS-induced increases in total SERT protein. Both unstimulated and LPS-stimulated activity was inhibited by the specific SERT inhibitor fluoxetine (IC50= 5-8 nM) and was reduced by the anti-inflammatory cytokine interleukin-10. Changes in extracellular concentrations of interleukin-lβ and tumor necrosis factor-α did not affect SERT activity.