Frontotemporal lobar degeneration (FTLD) can be pathologically subdivided into tau-positive and tau-negative types. The most common tau-negative variant is FTLD with ubiquitin-immunoreactive lesions (FTLD-U). Recently, the TAR DNA binding protein 43 (TDP-43) was identified in neuronal inclusions in FTLD-U. After applying TDP-43 immunohistochemistry to a series of 44 cases of FTLD-U with no secondary pathology, three cases (7%) were identified with ubiquitin- and p62-positive neuronal cytoplasmic inclusions (NCI) that were negative for TDP-43. All the three cases had marked brain atrophy with striking atrophy of the striatum. Cases 1 and 2 presented at ages 43 and 38, respectively, as behavioral variant frontotemporal dementia (1 with positive family history) and had ubiquitin- and p62-positive NCI in frontotemporal neocortex and dentate granule cells of the hippocampus. Case 3 presented with the corticobasal syndrome. Unlike the other two cases, ubiquitin- and p62-positive NCI were also visible on hematoxylin and eosin stain. There were no neuronal intranuclear inclusions. Electron microscopic examination of the NCI in cases 2 and 3 revealed granulofilamentous inclusions. These cases confirm the existence of TDP-43-negative FTLD-U and extend the clinical and pathological spectrum of this disorder. The findings raise the possibly of an as yet identified protein that may play a pathogenic role in tau-negative FTLD.