After aerosolization of a bovine strain of parainfluenza type 3 virus, the pathogenesis of the virus was followed from the trachea to the bronchioalveolar compartments of the lung of colostrum-free calves and of conventionally reared calves during a 5- to 12-day postexposure interval. By tissue titration, plaque assay, and electron microscopy, it was found that virus infection could be established in colostrum-free calves as well as in conventionally reared calves, even though sequential changes of virus replication were observed mainly in the infected colostrum-free calves during the 5- to 6-day postexposure periods. Electron microscopy demonstrations of (i) aggregates of viral nucleocapsids in the cytoplasm, (ii) alterations of cilia and basal bodies, (iii) dissolution of cytoplasmic membranes, and (iv) the shedding of virus into luminal spaces confirmed that epithelial cells of the respiratory tract were the primary target cells for the virus replication leading to cell destruction. These observations revealed further that productive infection was more efficient in the bronchioalveolar regions than in the tracheal regions, although large aggregates of viral nucleocapsids and destructive changes were more pronounced in the tracheal epithelium. The finding that parainfluenza type 3 virus replicates in the alveolar type II cells suggests that changes in surfactant production may occur during the peak of infection of these cells. The demonstration of virus budding through the basement membrane of small bronchioles and the presence of virus particles in the interstitial regions imply that one of the host defense lines, the basement membrane, may be impaired by virus invasion.