The transcription factors C/EBPα and C/EBPβ belong to the leucine-zipper C/EBP (CCAAT/enhancer binding protein) family of DNA-binding proteins. C/EBPα and C/EBPα are expressed in the liver and are implicated in the control of transcriptional events following sepsis. It is hypothesized that inhibition of C/EBPα gene expression following sepsis may lead to some of the phenotypic features we recognize as sepsis syndrome such as decreased visceral protein (albumin) synthesis. In this study we demonstrate that C/EBPα mRNA accumulation is transiently inhibited 12 hr following peritoneal insult, consistent with previous data. However, we demonstrate that (1) there is increased binding of hepatic nuclear protein to the C/EBPα DNA response element 48 hr following insult, (2) a marked increase in C/EBPα protein is observed 48 hr following CLP insult compared with no increase in hepatic C/EBPα protein at 12 hr postinsult, (3) the increase in hepatic C/EBPα protein at 48 hr following cecal ligation and puncture is not associated with an increase in C/EBPα mRNA accumulation, (4) the increase in hepatic C/EBPα protein is associated with an increase in C/EBPβ protein, and (5) hepatic albumin mRNA accumulation is decreased at 12 and 48 hr following insult and does not correlate with the C/EBPα protein synthesis. We conclude that the possible role of the transcription factor C/EBPα with respect to decreased albumin gene expression following sepsis must be reevaluated.