A diagnosis of beta-mannosidosis, a lysosomal storage disease caused by a deficiency of beta-mannosidase, was made in 12 purebred Salers calves. Affected neonatal calves were unable to rise and had intention tremors, hidebound skin, slightly domed calvaria, slight prognathism, and narrow palpebral fissures. Postmortem findings included variable dilatation of the lateral cerebral ventricles, marked pallor and paucity of white matter of the cerebrum and cerebellum, and mild to marked bilateral renomegaly. Microscopic lesions consisted of clear, intracytoplasmic vacuoles, which were especially prominent in neurons, thyroid follicular cells, proximal renal tubular epithelium, and reticuloendothelial cells. By ultrastructural examination, the intracytoplasmic vacuoles were identified as membrane-bound lysosomes distended by lucent material. The serum of affected calves was profoundly deficient in beta-mannosidase. Oligosaccharides, principally a trisaccharide with a terminal hexose in the beta-anomeric configuration, accumulated in tissues of affected calves. The percentage (37.2) of affected calves from groups of siblings, the approximately equal sex ratio, and the phenotypic normalcy of the parents of affected calves are compatible with an autosomal recessive mode of inheritance typical of other glycoproteinoses.