Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.