Background/Aims: Several previous studies have suggested that interferon. gamma (IFN gamma) may play a key role during hepatic progenitor cell (HPC) mediated liver regeneration. However to date, no studies have directly tested the ability of IFN gamma to mediate the HPC response in an in vivo model.Methods/Results: Administration of IFN gamma 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 IFN gamma-treated, CDE-fed mice, demonstrating that liver damage was exacerbated in these animals. Administration of IFN gamma to control diet fed mice did not induce liver damage, however it did stimulate hepatic inflammation.Conclusions: Our results suggest that IFN gamma 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. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.