Abstract: Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. Limited evidence suggests that antibodies can protect humans against lethal CCHFV disease, but the protective efficacy of antibodies has never been evaluated in adult animal models. Here adult mice were used to investigate the protection provided by glycoprotein-targeting neutralizing and non-neutralizing monoclonal antibodies (mAbs) against CCHFV infection. A single non-neutralizing antibody (mAb-13G8) was identified that protected adult type I interferon deficient mice >90% when treatment was initiated prior to virus exposure and >60% when administered after virus exposure. Neutralizing antibodies known to protect neonatal mice from lethal CCHFV infection, failed to confer protection regardless of IgG subclass. The target of mAb-13G8 was identified as GP38, one of multiple proteolytically-cleaved glycoproteins derived from the CCHFV glycoprotein precursor polyprotein.