We analyzed a family of proteins from hepatoma cell nuclei that bind to interleukin-6 responsive elements (IL-6REs) of several acute-phase genes. This family is characterized by leucine zipper domains compatible with that of the CCAAT/enhancer binding protein (C/EBP). A cDNA clone coding for a member of the family, IL-6DBP, was isolated; it is strongly homologous to C/EBP in the region of the basic domain and in the leucine zipper sequence. IL-6DBP and C/EBP can interact in vitro to form heterodimers that bind to DNA with the same specificity as the respective homodimers, and they can interact functionally in vivo. Both the DNA binding activity and the trans-activating capacity of IL-6DBP are induced in hepatoma cells by treatment with IL-6 through a posttranslational mechanism, implicating it as a nuclear target of IL-6 and as a mediator of the IL-6-dependent transcriptional activation of liver genes during the acute-phase response.