The distribution of reactive astrocytes was examined in the cortical gray matter of non-motor and motor regions from cases of familial and sporadic amyotrophic lateral sclerosis (ALS) and compared to that of beta-amyloid deposits. By glial fibrillary acidic protein immunocytochemistry, patches of reactive astrocytes, characterized by multiple reactive astrocytes in a circular or patch-like formation, occurred in 12 of 15 ALS cases examined. These patches of reactive astrocytes were not restricted to the motor cortex but were found in the gray matter in ALS in all examined brain regions, including frontal, temporal, inferior parietal, cingulate, occipital, and motor cortices, from both familial and sporadic ALS cases. Reactive astrocytes were also found in the subpial region and at the gray/white matter junction. Because patches of astrocytes can occur in association with senile plaques, beta-amyloid was localized. By immunostaining, beta-amyloid deposits were observed in five of the 15 ALS cases: three cases had only early plaques, two had both early and classic plaques. The number of ALS cases with both astrocyte patches and amyloid plaques was four of 15, but typically astrocyte patches in ALS occurred without any evidence of an association with beta-amyloid deposits. Therefore, the astrocyte patches in ALS are not the result of beta-amyloid deposition. The widespread occurrence of reactive astrocytes, as patches in the cortical gray matter and in the subpial region and at the gray/white matter junction, is evidence of a widespread pathology in ALS cortex in both familial and sporadic forms of the disease.