Hereditary inclusion body myopathy associated with early-onset Paget disease of bone and frontotemporal dementia (hIBMPFTD) is a degenerative disorder caused by single substitutions in highly conserved residues of p97/VCP. All mutations identified thus far cluster within the NH 2 domain or the D1 ring, which are both required for communicating conformational changes to adaptor protein complexes. In this study, biochemical approaches were used to identify the consequences of the mutations R155P and A232E on p97/VCP structure. Assessment of p97/VCP oligomerization revealed that p97 R155P and p97 A232E formed hexameric ring-shaped structures of∼ 600 kDa. p97 R155P and p97 A232E exhibited an∼ 3-fold increase in ATPase activity compared to wild-type p97 (p97 WT) and displayed increased sensitivity to heat-induced upregulation of ATPase activity. Protein fluorescence analysis provided evidence for conformational differences in the D2 rings of both hIBMPFTD mutants. Furthermore, both mutations increased the proteolytic susceptibility of the D2 ring. The solution structures of all p97/VCP proteins revealed a didispersed distribution of a predominant hexameric population and a minor population of large-diameter complexes. ATP binding significantly increased the abundance of large-diameter complexes for p97 R155P and p97 A232E, but not p97 WT or the ATP-binding mutant p97 K524A. Therefore, we propose that hIBMPFTD p97/VCP mutants p97 R155P and p97 A232E possess structural defects that may compromise the mechanism of p97/VCP activity within large multiprotein complexes.