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.