The gp130 cytokines, including IL-6, IL-11, LIF and OSM, have important roles in neuroinflammation and neurodevelopment. However, the nature of any cell-specific responses of astrocytes and microglia to this family of cytokines and their molecular basis are not well understood. Here, the expression of the gp130 family cytokine receptors and subsequent signal pathway activation were examined in murine astrocytes and microglia in vitro. Astrocytes had high levels of OSMR mRNA and lower levels of IL-6R, LIFR and IL-11R mRNAs. In contrast, microglia expressed higher levels of IL-6R mRNA, similar levels of LIFR and IL-11R mRNAs, and no detectable OSMR mRNA. The OSMR protein was present in astrocytes but was undetectable in microglia. Conversely, the IL-6R protein was present in microglia but not detectable in astrocytes. In astrocytes, OSM induced STAT1 and STAT3 phosphorylation to a greater extent than hyperIL-6 (IL-6 linked to the soluble IL-6 receptor) and LIF. Conversely, hyperIL-6 and LIF but not OSM, induced phosphorylation of STAT1 and STAT3 in microglia. Upregulation of OSMR occurred in astrocytes, in response to a number of inflammatory mediators (e.g. lipo-polysaccharide) but remained undetectable in microglia. In contrast, the OSM mRNA was induced by the same inflammatory mediators in microglia but not astrocytes. Furthermore, the same inflammatory mediators also differentially induced other gp130 cytokines and their receptors between the two cell types. These findings show: (1) differences exist in the receptor expression utilized by the gp130 family of cytokines in astrocytes and microglia, (2) a molecular basis for the differential response to OSM by astrocytes versus microglia, and (3) a potential regulatory network exists between astrocytes and microglia in the central nervous system involving OSM and other gp130 cytokines.