Infection with murine gammaherpes virus 68 has become an accepted model for studying the virus/host interactions with regard to gammaherpes virus infections. Previous studies using gene deficient mice have revealed that neither IFNγ nor perforin are essential in controlling the course of infection or the virus load during chronic infection in C57BL/6 mice. However, transient multiorgan fibrosis and splenic atrophy is observed in mice lacking IFNγ or the IFNγ receptor. To study the interplay between perforin and IFNγ in controlling the virus-induced pathology and the viral load during chronic gamma herpes virus infection, we infected IFNγ/perforin double deficient C57BL/6 mice and followed the outcome of infection. While absence of perforin prevented the splenic atrophy in IFNγ deficient mice, fibrosis did not disappear. Moreover, double deficient mice developed extreme splenomegaly, were unable to control the viral load and displayed chronic immune activation. Thus IFNγ and perforin act in concert to minimize pathology and control the viral load in mice chronically infected with MHV68. Furthermore, while certain aspect of the virus-induced pathology in IFNγ deficient mice may be alleviated in double deficient mice, other aspects are exaggerated, and the normal architecture of the spleen is completely destroyed. Thus, IFNγ and perforin work in concert to minimize pathology and control the viral load. In the absence of both effector molecules, the balancing race between the virus and the host is tipped in favour of the virus causing chronic immune activation and fatal disease. This article is protected by copyright. All rights reserved.