Antidepressants are known to impact on the immune system. In this study, we examined the immunomodulatory properties of venlafaxine, a selective serotonin/norepinephrine reuptake inhibitor (SNRI), in murine experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated CNS demyelinating disease model of multiple sclerosis. EAE was induced in SJL/J mice by adoptive transfer of myelin-specific T cells. Mice received different doses of venlafaxine before induction and after onset of disease. Sustained daily oral treatment with 6, 20 and 60 mg/kg significantly ameliorated the clinical symptoms of the disease compared to vehicle during both preventive and therapeutic intervention. Venlafaxine suppressed the generation of pro-inflammatory cytokines IL-12 p40, TNF-alpha and IFN-gamma in encephalitogenic T-cell clones, splenocytes and peritoneal macrophages in vitro. It also diminished mRNA expression of a number of inflammatory genes in the inflamed CNS tissue, among them CD3, CD8, Granzyme B, IL-12 p40, IFN-gamma, TNF-alpha and the chemokines Ccl2 and RANTES, whereas the expression of brain-derived neurotrophic factor was increased. These findings demonstrate the strong immunomodulatory property of the selective SNRI venlafaxine. Further studies are warranted to clarify whether venlafaxine may exert similar effects in humans.