We report a retrospective case series of four patients with genetically confirmed Huntington's disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50's in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.