Human parainfluenza virus 3 replicates well in the noses and lungs of two species of cotton rats, Sigmodon hispidus and Sigmodon fulviventer. Peak viral titers of nearly 10(6) PFU/g are reached 2 days after infection in both tissues, are maintained through day 5, and are equivalent in the two species. Infectious virus is eliminated by day 8 after infection. Both species produce a strong neutralizing antibody response with titers of 1:10,000 4 weeks after infection. Viral replication in the nasal epithelium results in only minor histological changes, and viral antigen is found only in the apical portion of epithelial cells. Infection of S. hispidus causes a bronchiolitis with a peribronchiolar lymphoid cell infiltration that reaches a peak 6 days after infection, and there is only a minor component of interstitial pneumonia. In contrast, infection of S. fulviventer causes an interstitial pneumonia, and this lesion reaches its maximal extent by 6 days after infection. There is minimal peribronchiolar lymphoid cell infiltration in infected S. fulviventer. Lung lesions in both species of cotton rats are largely healed 9 days after infection, and the lungs are indistinguishable from those of uninfected controls 16 days after infection. These species of cotton rats offer separate models for the two major pulmonary manifestations of human parainfluenza virus 3 infection. The models may be useful for basic studies of the pathogenesis of this infection and for initial evaluation of candidate vaccines.