Apoptotic cell death in the liver in response to activation of the Fas pathway has been implicated in human disease states as well as liver remodeling and tissue repair. C/EBPβ, a member of the CCAAT enhancer binding protein family of bZIP transcription factors has been linked to both growth response and apoptotic targets in the liver, and, therefore, is a likely candidate for the regulation of apoptotic liver injury. We investigated differences in apoptotic cell death in the livers of C/EBPβ‐null mice using the Jo‐2 agonistic anti‐Fas antibody. Apoptotic injury was dramatically reduced in C/EBPβ −/− livers as shown by a nearly 20‐fold reduction in apoptotic hepatocytes 6 hours post‐Jo‐2 treatment in C/EBPβ −/− hepatocytes compared with controls (P < .04) and reduced activation of caspase 3. Bid cleavage occurred in Jo‐2 treated C/EBPβ −/− livers indicating a block of Fas‐induced injury distal to the death‐inducing signaling complex. The level of the antiapoptotic protein bcl‐x_L was increased greater than tenfold in the mutant animals (P < .04), which can, at least in part, account for the protection from Fas‐mediated apoptosis. In contrast, bcl‐x_L mRNA levels were unchanged. These observations link C/EBPβ to Fas‐induced hepatocyte apoptosis through a mechanism that likely involves translational or posttranslational regulation of bcl‐x_L.