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Orthohantaviruses are emerging zoonotic viruses that can infect humans via the respiratory tract. There is an unmet need for an in vivo model to study infection of different orthohantaviruses in physiologically relevant tissue and to assess the efficacy of novel pan-orthohantavirus countermeasures. Here, we describe the use of a human lung xenograft mouse model to study the permissiveness for different orthohantavirus species and to assess its utility for preclinical testing of therapeutics. Following infection of xenografted human lung tissues, distinct orthohantavirus species differentially replicated in the human lung and subsequently spread systemically. The different orthohantaviruses primarily targeted the endothelium, respiratory epithelium and macrophages in the human lung. A proof-of-concept preclinical study showed treatment of these mice with a virus neutralizing antibody could block Andes orthohantavirus infection and dissemination. This pan-orthohantavirus model will facilitate progress in the fundamental understanding of pathogenesis and virus-host interactions for orthohantaviruses. Furthermore, it is an invaluable tool for preclinical evaluation of novel candidate pan-orthohantavirus intervention strategies. Author summary: Orthohantaviruses are rodent-borne pathogens that can be transmitted from rodents to humans by inhalation of aerosolized virus-contaminated rodent excreta. While orthohantaviruses generally do not cause overt clinical signs in rodents, orthohantavirus infection can lead to severe disease with case fatality rates up to 40%. The pathogenesis of associated hemorrhagic fever with renal syndrome (HFRS) mainly in Europe and Asia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas remains poorly understood. Particularly the understanding of the early steps of pathogenesis occurring in the human lungs is limited. In addition, assessment of the efficacy of cross-reactive anti-orthohantavirus antibodies is severely hampered by the limited availability of in vivo models that allow for replication of both HFRS- and HCPS-associated orthohantaviruses within the same animal model. Therefore, we present a human lung xenograft mouse model to study early events of orthohantavirus pathogenesis in the human lung. We demonstrated that multiple orthohantaviruses replicate inside the human lung xenografts, and characterized the tropism and host responses within these human lung xenografts. Also, as a proof-of-principle, we showed that the model can be utilized to assess the protective efficacy of an existing monoclonal antibody against Andes virus infection. Overall, this pan-orthohantavirus model allows for the study of orthohantavirus pathogenesis and will aid as a novel platform to test anti-orthohantavirus countermeasures. [ABSTRACT FROM AUTHOR]