Rationale: A runaway inflammatory response to systemic infection or severe trauma is characterized by the activation of a diversity of pathways, ultimately resulting in the development of DIC and multi-organ failure. Objectives: Despite increased fundamental knowledge of the pathogenesis of DIC, the exact molecular mechanisms remain elusive. We aimed therefore to improve our understanding of the molecular pathways underlying endotoxin-induced DIC. Methods: We performed large-scale gene expression profiling in the liver of mice during the onset of endotoxin-induced DIC. The relevance of an identified candidate gene involved in endotoxin-induced DIC was subsequently assessed in the generalized Shwartzman reaction. Measurements and Main Results: About 5% of over 20.000 genes were differentially regulated. In addition to well-established sepsis-associated genes like MIP-1, PAI-1, CD14 and A20, we identified several novel candidates for inflammatory disease of which the transcription factor C/EBP was studied further. Induction of DIC in C/EBP deficient mice decreased endotoxin-induced systemic inflammation as compared to wildtype mice, as evident from decreased plasma levels of TNFa and IL-6. In addition, C/EBP deficiency also partly protected against DIC-induced mortality. Interestingly, C/EBP deficiency seemed mainly protective by improving renal function. This latter notion confirmed in an experimental model of renal ischemia/reperfusion injury (I/R) in which C/EBP deficiency reduced I/R-induced creatinine and urea levels. Conclusions: Our results endorse the usefulness of gene expression profiling in identifying novel mediators of DIC by showing that C/EBP regulates specific pathological features of this endotoxin-induced syndrome.