In the nervous system, glucocorticoids exert beneficial or noxious effects, depending on their concentration and time-exposure. They act via the glucocorticoid receptor (GR) which recruits the p160 coactivators (SRC-1, SRC-2 and SRC-3). It was often shown that the three SRCs are interchangeable. The aim of the present study was to evaluate if the GR-SRCs interactions are dependent on several parameters like the target promoter structure, cell type or exogenous stressful parameters like hypoxia. We investigated the GR-SRCs interactions in two glial cells: astrocytes for the central nervous system and Schwann cells for the peripheral nervous system. We have shown by performing functional studies (overexpression and siRNA knock-down) that the recruitment of the three p160 by the GR is promoter-dependent and cell-specific. Moreover, we have shown that hypoxia (5% of oxygen) enhanced GR transactivation in both glial cells. Although hypoxia enhanced GR transactivation, it did not alter the interactions between the GR and the three p160s. Finally, we have shown that the potentiation of GR transactivation by hypoxia is due to an increase of the GR transcripts in Schwann cells but not in astrocytes. Altogether, these results reveal that the p160s are not interchangeable and that their recruitment by the GR is a multiparametric event.