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Filoviruses of the genus Ebolavirus include 6 species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case fatality rates can range between 0% and 90%. In order to understand the molecular basis of these differences, it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Nonhuman primates (NHPs) are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHPs. Here we used HLA-A2–transgenic, NOD–scid–IL-2γ receptor–knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While markedly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, the case fatality ratios of different Ebolavirus species in humans were recapitulated in the humanized mice. Our findings point to humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and suggest that further investigations on Reston virus pathogenesis in humans are warranted., Humanized mice reconstituted with human hematopoiesis recapitulate the pathogenicity of all ebolaviruses.