Background: Experimental and clinical studies have reported increased levels of pro inflammatory cytokines in patients with major depressive disorder (MDD), suggesting that immune system dysregulation may contribute to MDD pathophysiology. Aim: Due to the lack of knowledge about the immune potential of antidepressants, this study investigated the immunomodulatory effects of bupropion, a norepinephrine–dopamine reuptake inhibitor. Methods: This study involved 18 patients with MDD treated with bupropion (150 mg/d) for 4 weeks and 23 healthy volunteers. All participants underwent multiplex bead based cytokine assessment before and after bupropion treatment to quantify the following cytokines: interleukin (IL) 1β, IL 2, IL 4, IL 5, IL 6, IL 7, IL 8, IL 10, IL 12, IL 13, IL 17, interferon γ, tumor necrosis factor α, granulocyte colony stimulating factor, granulocyte macrophage CSF, monocyte chemotactic protein 1, and macrophage inflammatory protein 1β. Results: Four week treatment with bupropion significantly increased the levels of IL 1β (P = 0.011), IL 4 (P = 0.019), IL 5 (P = 0.019), IL 7 (P = 0.021), and IL 8 (P = 0.023) compared to the control group. Furthermore, the percentage change in most cytokines, including anti inflammatory cytokines such as IL 4, IL 5, IL 10, and IL 13, was significantly increased after bupropion treatment. Conclusion: The promoted synthesis of anti inflammatory cytokines to surpass the pro inflammatory cytokines may be a crucial step in the treatment of MDD patients with bupropion.