The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4α (HNF-4α), in livers of rats. HNF-4α is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4α is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4α, HNF-1α, was reduced. Interleukin-1β (IL-1β) is a cytokine whose levels are increased in vivo in response to LPS. IL-1β resulted in a decrease in HNF-4α levels in HepG2 cells. This IL-1β–induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4α that occurs in vivo after the administration of LPS may be the result of IL-1β–induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1β antagonists or proteasome inhibitors might increase HNF-4α protein levels in the acute-phase response, which could result in increased liver function and survival.