The murine papovavirus K causes fatal pneumonia in infant mice, but an asymptomatic infection in older mice. In order to establish whether the virus affects the central nervous system in the course of systemic infection, we carried out morphological and immunohistochemical studies on the experimentally infected mice. BALB/c mice, less than 4 days of age, were inoculated with K virus either intraperitoneally or intracerebrally. When the animals were moribund, usually 10 days or so, after inoculation, their brains were removed and examined. Acutely infected mice showed only minor changes: intranuclear eosinophilic inclusions in very rare capillary endothelial cells of the brain. However, immunoperoxidase studies, using specific antibody to K virus, revealed that a number of brain cells had positive nuclear staining. These nuclei were distributed throughout the brain, without an apparent site of predilection. Double-immunostaining showed that virtually all cells whose nuclei were positive for viral antigen were endothelial, because their cytoplasm was positive for factor-VIII or vimentin. There were no nuclei positive for viral antigen in astrocytes, as determined by positive staining for glial fibrillary acidic protein or glutamine synthetase. By electron microscopy, clusters of K virus particles were found only in the nuclei of brain capillary endothelial cells. Although these endothelial cells showed degeneration of varying degree, their basement membranes remained relatively intact and there was no disorganization in the endfeet of contiguous astrocytes. Neurons and glial cells had normal ultrastructures. Therefore, this study has demonstrated that there is involvement of central nervous system during systemic K virus infection and that the infection involves predominantly brain capillary endothelial cells.