TAR DNA binding protein (TDP-43) is the pathologic substrate of neuronal and glial aggregates in amyotrophic lateral sclerosis (ALS). Pathologic TDP-43 is hyperphosphorylated and cleaved to generate abnormal protein species that accumulate in the cytoplasm. To assess the hypothesis of TDP-43 pathology as a systemic disorder in ALS we analysed the immunohistochemical and biochemical profile of TDP-43 in muscle biopsies of 30 ALS patients and 30 controls. In all ALS muscle biopsies we observed that TDP-43 was constantly present in an intranuclear localization and TDP-43 Western blotting showed only a 43-KDa band as controls. Our results suggest that TDP-43 pathology is probably confined to the central nervous system in ALS.