Murine gammaherpesvirus-68 (MHV-68) infection in interferon-γ receptor knockout mice (IFN-γR −/ −) results in splenic fibrosis and excessive loss of splenocytes. In our present study we found that MHV-68 infection in IFN-γR −/ − mice also resulted in fibrosis and atrophy of the mediastinal lymph nodes, interstitial pulmonary fibrosis and fibrotic changes in the liver. Atrophy and cellular depletion of the spleen in IFN-γR −/ − was not the result of increased cell death. The loss of splenocytes in IFN-γR −/ − mice, which was most evident on day 23 after infection, correlated with an increase in the number of leukocytes in peripheral blood. At the peak of leukocytosis, on day 23 after infection, peripheral blood cells from infected IFN-γR −/ − mice were unable to traffic through the fibrosed spleens of IFN-γR −/ − mice but were able to enter the spleens of wild-type mice. This indicates that leukocytosis was in part the result of emigration of cells from the spleen and their subsequent exclusion of re-entry at the height of fibrosis. Significant cytokine and chemokine changes were observed in spleens of IFN-γR −/ − mice. IFN-γ, tumor necrosis factor-α (TNF-α ), TNF-β, interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), lymphotactin, and MIP-1β were elevated on day 14 after infection whereas chemokines IP-10 and MIG were significantly reduced. These changes suggest a role for dysregulated cytokines and chemokines in severe organ-specific fibrosis with implications for immune-mediated fibrotic disorders.