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The role of interferon in the protection of mice from Rift Valley fever (RVF) virus was investigated. Female, ICR mice were injected intramuscularly with either human interferon gamma (HuIFN-gamma), mouse interferon gamma (MuIFN-gamma), MuIFN-gamma attached to polystyrene (PS), or interleukin-2 (IL-2). The mice were then infected with RVF virus and the survival rate was monitored. It was found that only mice treated with MuIFN-gamma attached to PS survived. Further, those treated with both MuIFN-gamma and PS as well as IL-2 survived. In a competitive assay between the viral antigen and anti-RVF IgM monoclonal antibody, only anti-RVF IgM antibody was able to protect mice from RVF virus. However, this protection was found only in mice treated with MuIFN-gamma. The neutralization of RVF virus by anti-RVF IgG antibody was not observed. It was suggested that the protection mediated by anti-RVF IgM monoclonal antibody was dependent on the presence of MuIFN-gamma.