Intranasal infection of Balb/c mice with 106 plaque forming units (PFU) of wild-type cowpox virus (CPV) and rabbitpox virus (RPV) induced strikingly different pulmonary pathology despite nearly identical clinical signs of illness and LD50. Intranasal infection with CPV induced severe peribronchial, peribronchiolar, and perivascular hemorrhage with a mixed inflammatory cell infiltrate, bronchial and bronchiolar epithelial cell hyperplasia with intracytoplasmic acidophilic inclusion bodies, and alveolar hemorrhage and edema. In contrast, infection with RPV induced a mixed peribronchial and peribronchiolar inflammatory cell infiltrate, multifocal areas of bronchiolar epithelial cell coagulation necrosis, alveolar edema, and a conspicuous absence of pulmonary hemorrhage. Viremia was not detected following CPV infection and only 1 of 11 mice had brain-associated virus at death. Mice infected with RPV exhibited a viremia 2-3 days after infection and all mice had virus associated with the brain at death. Mice infected with viruses containing certain serine protease inhibitor (SPI) gene mutations (CPV delta SPI-1, CPV delta SPI-3, and RPV SPI-1-) exhibited no difference in clinical disease manifestation when compared with those infected with wild-type viruses. However, inactivation of the SPI-2 genes in either CPV or RPV resulted in disease attenuation and alteration of pulmonary pathology. Mice infected with the CPV delta SPI-2 mutant showed decreased pulmonary hemorrhage, reduced inflammation, and an absence of alveolar edema, while mice infected with the RPV delta SPI-2 mutant had a marked increase in intrapulmonary inflammatory cells and only a transient viremia.