To establish a model for SARS, female Balb/cJ mice were inoculated with five strains of MHV intranasally (105 PFU/mouse). MHV-1-infected A/J mice developed pulmonary edema, hyaline membranes and alveolar exudates similar to SARS lung disease in humans and all infected mice died by day 8 p.i. By real-time RT-PCR, susceptible A/J mice developed a reduced type I interferon response in comparison to C57BL/6 mice whereas significantly higher cytokine levels, particularly macrophage chemoattractant protein-1 (MCP-1) were seen in A/J mice compared to resistant C57BL/6 mice. A/J mice vaccinated with MHV-3 and then subsequently challenged with MHV-1 all survived infection. These studies describe a potentially useful small animal model of human SARS, which can now be utilized to define the immunopathology of SARS and to examine treatment strategies.