Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, and progressive neurodegenerative disorder with no cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS; and aggresome formation of misfolded SOD1 is closely associated with ALS pathogenesis. HDAC6, one of the histone deacetylase family members, has already been demonstrated to play an important role in regulating aggresome formation of misfolded proteins and protecting cells against the toxicity induced by misfolded proteins. In this study, we found that in a cellular model with impaired proteasome activity, the TAR DNA-binding protein 43, which is closely linked with ALS and associated with various neurodegenerative disorders such as frontotemporal lobar degeneration, Alzheimer’s disease, and Parkinson’s disease, can regulate mutant SOD1 aggresome formation through an HDAC6-dependent manner. TDP-43 deficiency did not affect poly-ubiquitination of mutant SOD1, whereas it greatly decreased the expression level of HDAC6, which is required for aggresome formation of ALS-linked mutant SOD1. Moreover, overexpression of siRNA-resistant HDAC6 restored mutant SOD1 aggresome formation in TDP-43-knockdown cells. Thus, our data provide evidence that TDP-43 plays an important role in mutant SOD1 aggresome formation through its regulation of HDAC6.