Muscle biopsy specimens from 15 autopsied patients with the isolated form of amyotrophic lateral sclerosis were examined by routine histological and immunocytochemical methods using a panel of monoclonal antibodies directed against differentiation and activation markers of immunocompetent cells. In 12 cases, cellular infiltrates consisting mainly of T-cells and macrophages were seen. Both CD8+ and CD3+ cells, in juxtaposition with OKM1+ macrophages, were particularly seen in the atrophied parts of muscle. The majority of the T-cells appeared to be of the CD4+ T-helper/inducer type, whereas the CD8+ T-suppressor/cytotoxic cells were only rarely and focally present. On the other hand, B-, NK- and K-cells were infrequently seen. Most of the T-cells and macrophages surrounding the atrophied muscle fibers were in an activated state, as indicated by their intense HLA DR expression. In addition, some angulated degenerated fibers showed strong endomysial positivity for HLA DR in the regions where T-cells and macrophages were present in clusters. The immunoreactive changes in ALS-associated muscle atrophy are very similar to those reported for exercise-induced damage and some forms of myositis. The present study shows that the expression of major histocompatibility complex products and the relative numbers of infiltrating immunocompetent cells are closely associated with the extent of destruction of muscle fibers in ALS.