Sections of the spinal cord from 10 patients with classic amyotrophic lateral sclerosis and from 10 control cases were examined by immunocytochemical methods to localize metallothionein. Metallothionein immunoreactivity was seen in the nucleus and cytoplasm of a subset of astrocytes, largely confined to the gray matter. Also, diffuse gray matter staining was observed, probably representing small glial fibers. Astrocytic metallothionein immunoreactivity (P less than 0.01) and strong gray matter matrix staining (P less than 0.03) was increased in the spinal cords from patients with amyotrophic lateral sclerosis. Although compatible with induction by metals, increased metallothionein expression in the spinal cords from patients with amyotrophic lateral sclerosis may also have resulted from inflammation or gliosis.