Central nervous system (CNS) tissue was studied by immunocytochemistry and electron microscopy from three cases of multiple sclerosis (MS) in which evidence of ongoing myelin breakdown could be documented. The study focussed upon the role of glial cells in the pathogenesis of demyelination. In acute MS, demyelination involved the vesicular dissolution of myelin from intact axons and a paucity of fibrillary astrogliosis. Foamy macrophages, many of them probably derived from transformed and recently proliferated microglia, contained recognizable myelin debris and lipid droplets and were abundant throughout the lesions. These cells formed the major phagocytic population and stained positively for class II major histocompatibility complex antigens (HLA-DR; Ia). In acute MS lesions, rounded astrocytes were encountered which possessed membrane-bound compartments enclosing phagocytosed fragments of myelin basic protein-positive debris. Despite the superficial resemblance of these cells to foamy macrophages, the presence of intermediate filaments, glycogen granules and diffuse glial fibrillary acidic protein positivity supported an astroglial identity. Astrocyte processes were involved in myelin removal and invested recently demyelinated axons. Hypertrophic fibrous astrocytes were common in chronic active lesions, were capable of myelin degradation and on occasion, contained myelin debris attached to clathrin-coated pits. These astrocytes were sometimes Ia+. Oligodendrocytes were depleted from the center of active lesions but were numerous at the lesion margin, suggesting survival and proliferation. They stained positively for myelin-associated glycoprotein, a marker for immature oligodendrocytes. However, they were invariably Ia-. The findings confirm and further support a role for the astrocyte as both an antigen presenting cell and a phagocyte in the CNS during MS.