Recently, 43-kDa TAR DNA-binding protein (TDP-43) was identified as a component of ubiquitinated inclusions (UIs) in sporadic amyotrophic lateral sclerosis (SALS). To clarify whether TDP-43 immunoreactivity is present in neuronal inclusions in familial ALS (FALS), we examined immunohistochemically the brains and spinal cords from four cases of FALS, two with Cu/Zn superoxide dismutase (SOD1) gene mutation and two without, together with three cases of SALS and three control subjects, using two antibodies, one polyclonal and one monoclonal, against TDP-43. Neuropathologically, the SOD1-related FALS cases were characterized by Lewy body-like hyaline inclusions (LBHIs) in the lower motor neurons. On the other hand, the SOD1-unrelated FALS cases showed degeneration restricted to the upper and lower motor neuron systems, with Bunina bodies (BBs) and UIs in the lower motor neurons, being indistinguishable from SALS. No cytoplasmic TDP-43 immunoreactivity was observed in the control subjects or SOD1-related FALS cases; LBHIs were ubiquitinated, but negative for TDP-43. UIs observed in the SALS and SOD1-unrelated FALS cases were clearly positive for TDP-43. BBs were negative for this protein. Interestingly, in these SALS and FALS cases, glial cells were also found to have cytoplasmic TDP-43-positive inclusions. These findings indicate that the histological and molecular pathology of SALS can occur as a phenotype of FALS without SOD1 mutation.