Adult animals harbor an abundant population of oligodendrocyte precursor cells (OPCs) whose functions, other than providing a pool of precursors for oligodendrocytes, are unknown. Previous studies have demonstrated that these unusual glial cells, which can be identified by virtue of their expression of the NG2 chondroitin sulfate proteoglycan, react to traumatic brain injury. To determine the generality of the ability of OPCs to react to neuropathological insults, we have examined the reactions of OPCs to infection of the brainstem with virulent and attenuated strains pseudorabies virus (PRV). When motor neurons within the dorsal vagal complex are infected with PRV, OPCs immediately adjacent to the infected neurons display dramatic reactive changes. These changes are characterized by (1) cell bodies that stain more heavily with antibodies against NG2 than do non-reactive OPCs, (2) an increased density of processes, and (3) the appearance of fine filopodia on the cell body and processes. The onset of these morphological changes was rapid, and they occurred simultaneously with the appearance of viral antigens in motor neurons. At late stages of infection, the soma of OPCs elaborated fewer processes. A small number of the reactive OPCs contain viral antigens. These findings extend the range of neuropathological situations to which OPCs react indicating that this cell population is extremely dynamic. They also suggest that the reaction of OPCs and the consequences of these reactions to brain function must be considered in any procedure, either experimental or clinical, in which viruses are introduced into the central nervous system.