Newborn mice were inoculated orally with 100 LD50 of K-papovavirus and the distribution of virus in fatally infected animals was studied by in-situ nuclei acid hybridization methods and immunoperoxidase staining for K virus capsid (V) antigen. Histopathologically, K virus produced extensive involvement of pulmonary endothelial cells, resulting in interstitial pneumonia, and widespread involvement of other endothelial cell populations throughout the systemic circulation. Endothelial cells in lungs, kidneys and other organs exhibited both specific hybridization for K virus nucleic acids and positive staining for K virus V antigen, indicative of productive infection. Scattered, apparently extravascular cells within brain parenchyma also exhibited both specific hybridization and immunohistological staining for K virus V antigen. In contrast, specific hybridization for K virus nuclei acids, in the absence of immunohistochemical labelling of K virus V antigen, suggesting transcription of viral DNA without expression of viral proteins, was detected in renal tubular epithelial cells and nonvascular, apparently lymphoid cells within the spleen and lymph nodes. The present study confirms the predominantly endotheliotropic nature of K virus infection in newborn mice and also demonstrates that the virus invades renal epithelial, lymphoid and possibly glial cells during primary infection.