Two guinea pigs (Cavia porcellus) were affected by an acute naturally developing lethal pneumonitis. One guinea pig was found dead and had not had clinical signs of disease, whereas the second guinea pig was dyspneic and tachypneic. Necropsy revealed well-demarcated areas of pulmonary consolidation in the cranial and ventral areas of the lungs. Necrotic bronchiolar epithelium accompanied by basophilic intranuclear inclusion bodies was the primary histopathologic finding. Transmission electron microscopy revealed virions with ultrastructural characteristics of an adenovirus. Adenoviral infections in guinea pigs are likely to be more prevalent than are currently recognized. Adenoviruses may cause inapparent infections in guinea pigs that could potentially interfere with laboratory studies.