Growing evidence indicates immunoregulatory effects of various antidepressants. Through the interaction of the nervous and immune systems, the norepinephrine-serotonin system was shown to modulate inflammatory CNS diseases. Thus, we examined the norepinephrine-serotonin reuptake inhibitor venlafaxine in an astroglia-microglia co-culture model which allows mimicking of an inflammatory milieu by increasing the cultured microglial fraction. Astrocytic membrane resting potential and intercellular coupling, two markers becoming severely impaired under inflammation, were assessed with the patch-clamp technique. We measured IL-6, IL-10, IFN-gamma and TGF-beta concentrations and analysed phenotypic changes of microglia. We found (i) a reversal of the inflammation-induced depolarization effect on the membrane resting potential, (ii) an augmentation of TGF-beta release with a concomitant reduction in the secretion of pro-inflammatory IL-6 and IFN-gamma, and (iii) a significant change of microglial phenotype from activated to resting morphology. Our data clearly indicate anti-inflammatory properties of venlafaxine which might be a result of monoamine-mediated immunomodulation.