NF‐IL6 is a nuclear factor that specifically binds to an IL1‐responsive element in the IL‐6 gene. In this study the gene encoding NF‐IL6 has been cloned by direct screening of a lambda gt11 library using NF‐IL6 binding sequence as a ligand. The full‐length cDNA encoded a 345 amino acid protein with a potential leucine zipper structure and revealed a high degree of homology to a liver‐specific transcriptional factor, C/EBP, at the C‐terminal portion. The bacterial fusion protein bound to the CCAAT homology as well as the viral enhancer core sequences as in the case of C/EBP. Recombinant NF‐IL6 activated the human IL‐6 promoter in a sequence‐specific manner. Southern blot analysis demonstrated the high‐degree conservation of the NF‐IL6 gene through evolution and the existence of several other related genes sharing the DNA‐binding domain. NF‐IL6 mRNA was normally not expressed, but induced by the stimulation with either LPS, IL‐1 or IL‐6. Interestingly, NF‐IL6 was shown to bind to the regulatory regions for various acute‐phase protein genes and several other cytokine genes such as TNF, IL‐8 and G‐CSF, implying that NF‐IL6 has a role in regulation not only for the IL‐6 gene but also for several other genes involved in acute‐phase reaction, inflammation and hemopoiesis.