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Most people infected with the mosquito-borne yellow fever virus (YFV) exhibit only mild symptoms, but the mortality rate of hospitalized patients is up to 50%. There is currently no approved treatment for YFV infection and although a live-attenuated prophylactic vaccine (YFV-17D) exists, immunization coverage remains low in some vulnerable populations, and it can cause uncommon severe side effects. Here, Ricciardi et al. screened 37 YFV-reactive monoclonal antibodies (mAbs) isolated from memory B cells of YFV-17D-immunized volunteers, and identified two that potently neutralized pathogenic laboratory-adapted and primary isolates of YFV in vitro. A single injection of either of the mAb candidates to hamsters three days post-infection prevented virus replication, protected from liver disease and significantly increased survival, without affecting weight gain. The mAbs were similarly effective in rhesus macaques, with a single intravenous dose administered two days after YFV infection protecting all 8 animals from death, whereas the 2 control animals required euthanasia 5 days post-infection. YFV RNA was undetectable in the serum and liver of treated macaques, and there were no signs of liver dysfunction.