Methylprednisolone (MP), a synthetic glucocorticoid agonist, is widely used for the clinical therapy of white matter diseases in the nervous system, such as spinal cord injury and multiple sclerosis. In addition to its potent anti-inflammatory and antioxidant properties, we recently discovered a selective antiapoptotic effect of MP on oligodendrocytes via the activation of the glucocorticoid receptor (GR) and the upregulation of bcl-X(L), a splicing isoform of the bcl-x gene. Based on published findings of the functional interactions between GR and STAT5, a transcription factor from the family of signal transducers and activators of transcription (STAT), we examined whether the glucocorticoid signaling pathway interacts with STAT5 to upregulate bcl-X(L) and protect oligodendrocytes. We show herein that (1) the GR and STAT5 complex is present on the STAT5-binding site of the bcl-x promoter region in oligodendrocytes; (2) the overexpression of an activated form of STAT5 prevents alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced oligodendrocyte cell death; and (3) this prevention is lost when the STAT5 gene is knocked down. Thus, our results provide one molecular mechanism underlying the postinjury protective effects of oligodendrocytes by stress hormones.