There are accumulating reports regarding poor response to the common antidepressant therapy. Antidepressant resistance has often been associated with activation of the inflammatory system. Accordingly, major depressive disorder (MDD) patients displaying inflammation prior to the treatment are less responsive to antidepressants. We hypothesized that the inefficacy of antidepressant therapy in some patients could be due to the drugs’ inflammatory mode of action that remained overshadowed by their substantial therapeutic value. Bupropion is a common-used antidepressant that is prescribed for seasonal affective disorders and smoking cessation as well. Nevertheless, there are some reports regarding inflammation induction and depressive behavior exacerbation in response to bupropion. Here, we put a spot on bupropion and investigate the alterations of innate and adaptive immunity cytokines and the influence on immune signaling pathways. Therefore, we treated LPS-stimulated human peripheral mononuclear cells (PBMCs) with different doses of bupropion. Pro-/ anti-inflammatory cytokines (TNF-ɑ, IL-1ß, IL-17, and IL-10) on both transcriptional and translational levels are assessed as well as the involvement of the JAK2 /STAT3, TLR2, and TLR4 signaling in this process. Bupropion decreased IL-17A, TNF-ɑ, and IL-1ß protein levels in the cultures. Nonetheless, the results regarding the target genes expression were controversial. Surprisingly, IL-1ß, TNF-ɑ, and IL-17A genes expression increased following bupropion treatment. TLR2, TLR4, JAK2, and STAT3 gene expression also rose in response to bupropion. Our findings suggest that bupropion possesses pro-inflammatory properties especially at concentrations of 50 and 100 and would rather be co-administrated with anti-inflammatory agents at least in patients with inflammatory conditions.