Electron microscopic studies of various tissues from virus-infected newborn mice disclosed a consistent form of viral cytonecrotic ultrastructural lesion in divergent types of cells (myocardial, valvular fibroblastic, aortic, exocrine and endocrine pancreatic, and hepatic cells) due to three different picornaviruses (coxsackieviruses B4 and B1 and encephalomyocarditis virus). The lesion is characterized by numerous membrane-vesicle complexes, margination of nuclear chromatin or nuclear pyknosis, dilation of rough endoplasmic reticulum, inflammation, and, at times, mitochondrial swelling. It seems apparent that the finding of this ultrastructural type of cytonecrosis is characteristic of a picornaviral infection regardless of the tissue involved and the offending member of the picornavirus group.