The inflammatory response represents a significant component of brain related disease responsible for neuronal degeneration. However, in some cases, inflammation is also a necessary first step during innate immune responses involved in mediating tissue repair. HMGB‐1 is a nuclear, non‐histone, DNA binding protein that is normally involved in chromatin stabilization and transcriptional regulation. It also has a well established role in mediating pro‐inflammatory events following passive release from necrotic neurons and glia. Similarly, C/EBPβ and C/EBPδ are nuclear transcription factors known to promote the expression of pro‐inflammatory genes following ischemic insult; and, both C/EBP β and C/EBP δ have been shown to mediate tissue repair following inflammatory stimuli in various cell types. Here, we report the results of our investigations into defining the role of C/EBP proteins in mediating the downstream signaling events that promote inflammation in response to passive HMGB‐1 release. Primary neurons and glia, subjected to hypoxia, were examined by Western analysis to determine the levels of C/EBPβ and C/EBPδ. In response to hypoxia, both C/EBP proteins were observed to be upregulated. In addition, cells treated with purified HMGB1 protein also showed an increase in C/EBP expression. Taken together, these data suggest that C/EBP proteins may function as downstream targets of HMGB1 signaling to promote HMGB1 mediated cellular responses to tissue injury.