C/EBPbeta is a leucine-zipper transcription factor believed to play an important role in the control of liver functions, and in particular in the transcriptional regulation of acute phase genes in response to several inflammatory stimuli and to recombinant cytokines. Moreover, this factor has been proposed as an important activator of several cytokine genes. We recently described the generation of mice in which the C/EBPbeta gene has been inactivated by gene targeting, showing that they are viable, but present specific defects in the myeloid and lymphoid compartments. Here we demonstrate that C/EBPbeta does indeed play a role in the transcriptional induction of some, but not all, liver acute phase genes. Activation is in particular defective in C/EBPbeta-deficient mice in the later phases of induction, suggesting that the early phases may be triggered by factors other than C/EBPs. Moreover, IL-6 activation is normal and TNFalpha activation is defective in the mutant mice, indicating a differential role of C/EBPbeta in the control of these two cytokines' production.