Hantavirus research is impeded by the absence of animal models of viral pathogenesis. We have studied the histopathology of mice (P. leucopus) naturally infected with the NY-1 hantavirus on Shelter Island, New York. Five mice were determined to be seropositive in Western blotting to Four Corners Virus nucleocapsid protein and had serum antibodies to Seoul and Puumala hantavirus antigens by immunofluorescence assay. Hantavirus gene segments of the NY-1 hantavirus were identified in these mice and shown to be 99% identical to hantavirus genes isolated from the Rhode Island patient with hantavirus pulmonary syndrome. In ultrastructural examinations, we identified hantavirus particles in pulmonary endothelial cells. Morphologically, these mice demonstrate lymphohistocytic infiltrates in hepatic portal zones and slightly increased numbers of immunoblasts in splenic red pulp. Additionally, the alveolar septa in the lungs of infected mice are edematous with hyperplasia of type 1 pneumocytes. Naturally infected P. leucopus may serve as potentially useful animal models of hantavirus pulmonary syndrome disease.