In the brain, osteopontin (OPN) may function in a variety of pathological conditions, including neurodegeneration, microcalcification, and inflammation. In this study, we addressed the role of OPN in primary and secondary neurodegeneration, microcalcification, and inflammation after an excitotoxic lesion by examining OPN knock-out (KO) mice. Two, four, and ten weeks after injection of the glutamate analogue ibotenate into the corticostriatal boundary, the brains of 12 mice per survival time and strain were evaluated. OPN was detectable in neuron-shaped cells, in microglia, and at the surface of dense calcium deposits. At this primary lesion site, although the glial reaction was attenuated in OPN-KO mice, lesion size and presence of microcalcification were comparable between OPN-KO and wild-type mice. In contrast, secondary neurodegeneration at the thalamus was more prominent in OPN-KO mice, and this difference increased over time. This was paralleled by a dramatic rise in the regional extent of dense microcalcification. Despite these differences, the numbers of glial cells did not significantly differ between the two strains. This study demonstrates for the first time a genetic model with co-occurrence of neurodegeneration and microcalcification, mediated by the lack of OPN, and suggests a basic involvement of OPN action in these conditions. In the case of secondary retrograde or transneuronal degeneration, OPN may have a protective role as intracellular actor.