Upon activation by liver injury, hepatic stellate cells produce excessive fibrous tissue leading to cirrhosis. The hepatotoxin CCl4 induced activation of RSK, phosphorylation of C/EBPβ on Thr217, and proliferation of stellate cells in normal mice, but caused apoptosis of these cells in C/EBPβ−/− or C/EBPβ-Ala217 (a dominant-negative nonphosphorylatable mutant) transgenic mice. Both C/EBPβ-PThr217 and the phosphorylation mimic C/EBPβ-Glu217, but not C/EBPβ-Ala217, were associated with procaspases 1 and 8 in vivo and in vitro and inhibited their activation. Our data suggest that C/EBPβ phosphorylation on Thr217 creates a functional XEXD caspase substrate/inhibitor box (K-Phospho-T217VD) that is mimicked by C/EBPβ-Glu217 (KE217VD). C/EBPβ−/− and C/EBPβ-Ala217 stellate cells were rescued from apoptosis by the cell permeant KE217VD tetrapeptide or C/EBPβ-Glu217.