The electron microscopic features of 11 stereotaxic brain biopsies that demonstrated inflammatory primary demyelination consistent both morphologically and clinically with multiple sclerosis are addressed. Degeneration of inner oligodendroglial loops and uniform widening of inner myelin lamellae antedated complete destruction of myelin sheaths. Perivascular lymphocytes, macrophages, and plasma cells were in intimate contact with myelin sheaths. Astrocytes proliferated even away from demyelinated areas. In areas of chronic, established demyelination, oligodendrocyte numbers were greatly decreased, and fields of completely demyelinated axons were seen among astrocytic processes. Axonal injury, evidenced by the formation of axonal swellings, was apparent in maximally affected areas. At the edge of acute lesions with demyelinated axons, oligodendrocytes were preserved morphologically. Thinly myelinated axons indicative of central nervous system-type remyelination by oligodendrocytes were observed primarily at the edges of plaques. An unusual inclusion observed in presumed macrophages was "polelike" bodies 0.04- to 0.7-microns thick. Linearly arrayed, their presumably proteinaceous crystalline substance was moderately electron-dense. Many were membrane-bound and appeared to arise from the endoplasmic reticulum. We conclude that disturbance of the myelinating function of oligodendrocytes may be a critical event in the pathogenesis of multiple sclerosis.