Objective Amyotrophic lateral sclerosis (ALS) is a fatal disorder of motor neuron degeneration. Most cases of ALS are sporadic (SALS), but about 5 to 10% of ALS cases are familial (FALS). Recent studies have shown that mutations in FUS are causal in approximately 4 to 5% of FALS and some apparent SALS cases. The pathogenic mechanism of the mutant FUS‐mediated ALS and potential roles of FUS in non‐FUS ALS remain to be investigated. Methods Immunostaining was performed on postmortem spinal cords from 78 ALS cases, including SALS (n = 52), ALS with dementia (ALS/dementia, n = 10), and FALS (n = 16). In addition, postmortem brains or spinal cords from 22 cases with or without frontotemporal lobar degeneration were also studied. In total, 100 cases were studied. Results FUS‐immunoreactive inclusions were observed in spinal anterior horn neurons in all SALS and FALS cases, except for those with SOD1 mutations. The FUS‐containing inclusions were also immunoreactive with antibodies to TDP43, p62, and ubiquitin. A fraction of tested FUS antibodies recognized FUS inclusions, and specific antigen retrieval protocol appeared to be important for detection of the skein‐like FUS inclusions. Interpretation Although mutations in FUS account for only a small fraction of FALS and SALS, our data suggest that FUS protein may be a common component of the cellular inclusions in non‐SOD1 ALS and some other neurodegenerative conditions, implying a shared pathogenic pathway underlying SALS, non‐SOD1 FALS, ALS/dementia, and related disorders. Our data also indicate that SOD1‐linked ALS may have a pathogenic pathway distinct from SALS and other types of FALS. ANN NEUROL 2010;67:739–748