Ischemia/reperfusion injury (IRI) is one of the main causes of liver dysfunction after liver surgery. Involvement of endoplasmic reticulum (ER) stress in various diseases has been demonstrated, and CAAT/enhancer binding protein–homologous protein (CHOP) is a transcriptional regulator that is induced by ER stress. It is also a key regulator of ER stress‐mediated apoptosis. The aim of this study was to investigate the role of CHOP in liver IRI. Wild type (WT) and CAAT/enhancer binding protein–homologous protein knockout (CHOP–/–) mice were subjected to 70% liver warm ischemia/reperfusion for 60 minutes. At different times after reperfusion, liver tissues and blood samples were collected for evaluation. Induction of ER stress including CHOP expression was ascertained. Liver damage was evaluated based on serum liver enzymes, liver histology, and neutrophil infiltration. Hepatocyte death including apoptosis was assessed. Liver warm IRI induced ER stress in both WT and CHOP–/– mice. In addition, CHOP expression was up‐regulated in WT mice. At 6 hours after reperfusion, liver damage was attenuated in CHOP–/– mice. On the basis of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick‐end labeling staining, apoptotic and necrotic cells were significantly reduced in CHOP–/– mice. CHOP deficiency also reduced the cleavage of caspase 3 and expression of the proapoptotic protein B cell lymphoma 2–associated X protein. Liver IRI induces CHOP expression, and CHOP deficiency attenuates liver IRI by inhibiting apoptosis. Elucidation of the function of CHOP in liver IRI may contribute to further investigation for a therapy against liver IRI associated with the ER stress pathway. Liver Transplantation 24 645–654 2018 AASLD.