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Rift Valley fever virus (RVFV) is a zoonotic arbovirus that causes severe disease in humans and ruminants. The infection is characterized by abortions in pregnant animals, high mortality in neonates as well as febrile illness in humans that develop in 1% of cases encephalitis or hemorrhagic fever. There is presently no specific antiviral treatment for RVFV infection available. In this study, two monoclonal antibodies (mAbs), raised against glycoprotein Gn, were applied in a therapeutic study. Treatment of RVFV infected mice with neutralizing mAb Gn3 alone at two different time points (30 minutes before or 30 minutes after virus challenge) showed only moderate efficacy of about 58.3% survival in both applications. However, a combination therapy together with non-neutralizing mAb Gn32 demonstrated complete protection (100% survival) when applied 30 minutes after the lethal challenge dose. The increase of mAb efficacy is probably based on cooperative neutralization effects. These data suggest that a combination therapy with mAbs Gn3 and Gn32 could be an effective treatment option against RVFV infection. Author summary: Rift Valley fever virus represents an acute viral disease affecting animals especially livestock and humans and is responsible for widespread outbreaks throughout Africa and on the Arabian Peninsula. The virus causes abortions and high mortality especially in young animals, whereas the symptoms in humans range from mild flu-like illness to severe hemorrhagic manifestations that can be lethal. So far, no antiviral therapeutics for animals nor humans were available yet. Therefore, we evaluated two monoclonal antibodies—one neutralizing and one non-neutralizing—in a mouse model for therapeutic treatment against Rift Valley fever. We selected these antibodies since they exhibited cooperative effects in vitro. During Rift Valley fever virus infection in mice, the applied neutralizing antibody alone showed only partial protection. In contrast, a combined application with both antibodies, lead to a complete protection in one treatment group (100% survival). A detailed pathological and molecular analysis clearly indicated a strong reduction of virus replication in target tissues of treated mice. Taken together, these results identified two monoclonal antibodies with strong antiviral effects against Rift Valley fever infection, which are promising candidates for therapeutic interventions against RVFV. [ABSTRACT FROM AUTHOR]