Interferon gamma (IFNγ) is an important mediator of inflammatory liver damage as part of a complex cytokine network. In vitro, IFNγ induces hepatocyte apoptosis. We hypothesized that the hepatocyte response to IFN signalling is context-dependent, and that specific growth factors, via phosphatidylinositol 3 kinase (PI(3)K) and protein kinase B/Akt signalling pathways, confer a cytoprotective effect. We established an in vitro model of IFNγ-mediated primary hepatocyte injury. We show that epidermal growth factor (EGF) and hepatocyte growth factor (HGF) attenuate the IFNγ-induced hepatocyte apoptosis. IRF-1, but not p53, is required for IFNγ-mediated apoptosis. The loss of p21waf−1 not only sensitizes the hepatocyte to IFNγ-mediated injury but is required for survival factor mediated cytoprotection. We show that the PI(3)K inhibitor, LY294002, partially inhibits the apoptotic response of the hepatocyte to IFNγ. In summary, we present evidence that a component of pro-apoptotic IFNγ signalling in the primary hepatocyte occurs via the PI(3)K pathway. We show that the hepatocyte response to IFNγ is modulated by external survival factors and that this survival signalling requires p21waf−1.