Background/Aims Several previous studies have suggested that interferon gamma (IFNγ) may play a key role during hepatic progenitor cell (HPC) mediated liver regeneration. However to date, no studies have directly tested the ability of IFNγ to mediate the HPC response in an in vivo model. Methods/Results Administration of IFNγ to mice receiving a choline deficient, ethionine (CDE) supplemented diet to induce chronic injury resulted in an augmented HPC response. This was accompanied by increased inflammation, altered cytokine expression and hepatic fibrosis. Serum alanine aminotransferase activity, hepatocyte apoptosis and Bak staining were significantly increased in IFNγ-treated, CDE-fed mice, demonstrating that liver damage was exacerbated in these animals. Administration of IFNγ to control diet fed mice did not induce liver damage, however it did stimulate hepatic inflammation. Conclusions Our results suggest that IFNγ increases the HPC response to injury by stimulating hepatic inflammation and aggravating liver damage. This is accompanied by an increase in hepatic fibrogenesis, supporting previous reports which suggest that the HPC response may drive fibrogenesis during chronic liver injury.