The current studies demonstrate complex and seemingly contradictory effects by gamma interferon (IFN-γ) on Friend virus (FV) infection. Both temporal and tissue-specific effects were observed. During the first week of infection, IFN-γ-deficiency caused increased levels of FV infection in multiple tissues. Surprisingly, however, by 2 weeks postinfection, IFN-γ-deficient mice had significantly lower levels of infection in both the spleen and bone marrow compared to wild-type mice. The rapid reduction of virus in the IFN-γ-deficient mice correlated with a more rapid virus-neutralizing antibody response than was observed in the wild-type mice. Furthermore, the virus-neutralizing antibody response in wild-type mice could be accelerated by ablation of their IFN-γ response. Although the IFN-γ-deficient mice developed an accelerated virus-neutralizing antibody response, they did not class-switch to immunoglobulin G class immunoglobulins nor could they maintain long-term virus-neutralizing antibody titers. Eventually, all of the IFN-γ-deficient mice failed to keep persistent virus in check and developed fatal FV-induced erythroleukemia.