Background: Paroxetine is one of the well-known antidepressants. Recent studies have focused on paroxetine’s probable immuno-modulatory effects, since findings have indicated inflammation’s role in the pathophysiology of depression. Therefore, in the present study, TLR2 and TLR4 mRNA genes expression was assessed in paroxetine-treated peripheral blood mononuclear cells (PBMCs). Methods: Venous blood samples were drawn from five healthy men (20-40 years old). Peripheral blood mononuclear cells (PBMCs) were isolated from samples and were cultured. After the first incubation for 24h, phytohemagglutinin plus lipopolysaccharide were added to the cells and then were incubated for 24h. Thereafter, cells were treated with different concentrations of paroxetine in the presence or absence of inhibitors of 5-HT2 and 5-HT7 receptors. After incubation for 48h, RNA was extracted and cDNA was synthesized. Using the real-Time PCR technique, TLR2 and TLR4 genes mRNA expression were evaluated. Statistical analysis of data were carried out using GraphPad Prism 7. Results: TLR2 and TLR4 mRNA expression were significantly increased in response to paroxetine at all concentrations. Furthermore, the co-culture of cells with the drug and the 5-HT2R and 5HT7R inhibitor simultaneously revealed that paroxetine’s immuno-modulatory effects viaTLR2 are dependent on serotonin, while it is independent of serotonin in the case of TLR4. Conclusion: Considering paroxetine’s effect in modulating immune responses via increasing TLR2 and TLR4 expression, paroxetine could have therapeutic potentials in diseases with a deficiency in these receptors.