Ideas concerning the nature of multiple sclerosis continue to be strongly influenced by the unusual morphology of the disease. A review of classic histology studies, however, reveals that there is less agreement than might be supposed concerning several important histiological features of the early lesion. Electron microscopy of brain biopsies, of immersion fixed autopsy tissue and of autopsy tissue fixed by early in situ brain perfusion suggests that the mechanism of demyelination in multiple sclerosis may be an unusual one that involves a progressive reduction in the number of myelin lamellae around nerve fibers in the vicinity of cells of uncertain origin that contain filamentous and multilamellated cytoplasmic inclusions unlike the usual pleomorphic inclusions seen in myelin phagocytes. Lymphocytes are not directly involved in this process but are observed to contact the inclusion material following its delivery to the Virchow-Robin spaces. The putative neurogenic or viral antigen in multiple sclerosis may be contained in this material. The occurrence of filamentous nuclei in early lesions fixed by immersion is an unrelated phenomenon, which may be an autolytic or drug induced artifact although this has not yet been established.