The cytokines interleukin-6 (IL-6) and interferon-α (IFN-α) are causally linked to distinct neuroinflammatory diseases, such as neuromyelitis optica and Aicardi-Goutières syndrome respectively. Transgenic mice that produce IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) in the CNS recapitulate many features of the respective human cerebral cytokinopathy. Microglia, the CNS-resident macrophages, are pivotal effectors of neuroinflammation and have a unique molecular signature. Microglia are highly plastic cells that can assume a variety of phenotypic states depending on signals from the surrounding environment. Here we investigated the phenotype of microglia in the GFAP-IL6 versus -IFN mice. Microglia in both transgenic mice showed ‘classical’ hallmarks of activation with increased Iba1 levels and tomato lectin binding. However, compared with WT, GFAP-IL6 and -IFN microglia had distinct morphologies. GFAP-IL6 microglia had significantly reduced and thicker processes, while GFAP-IFN microglia were hypertrophied with a significant increase in processes. GFAP-IL6 microglia were positive for pY-STAT3 but not pY-STAT1, while GFAP-IFN microglia were positive for pY-STAT1 but not pY-STAT3, consistent with activation of the specific signal transduction pathways and a direct response of these cells to the respective cytokines. Microglia from the GFAP-IL6 and -IFN mice displayed altered molecular signatures. GFAP-IL6 microglia had significantly reduced P2RY12 and markedly increased FCRLS and unchanged 4D4, while GFAP-IFN microglia had unchanged P2RY12 and 4D4 and slightly increased FCRLS. There was significant proliferation of microglia in GFAP-IL6 but not in WT or GFAP-IFN mice. These studies for the first time define the phenotype of microglia in response to IL-6 and IFN-α in the living CNS. The findings reveal dramatic differences in the morphological, molecular and proliferative properties of microglia in the CNS response to IL-6 versus IFN-α. These divergent microglia phenotypes may reflect unique functional roles and contributions of microglia to the distinct cerebral cytokinopathy mediated by these different cytokines.