The role of lysosomes in the pathogenesis of MS was studied by biochemical and ultrastructural techniques. Biochemical studies were performed on samples from 21 MS autopsies. The analyses included assays of acid proteinase, acid phosphatase, peptidase, neutral proteinase and esterase. The material for electron microscopy was obtained from ten biopsies made on MS patients during stereotaxic thalamotomy. In preliminary studies, the effect of autolysis on enzymatic activities was measured. These studies showed that acid hydrolases were stable enough to warrant further investigation. All enzyme activities studied were increased at the border zones of plaques, whereas in the macroscopically normal white matter only acid hydrolase activities were increased. Correspondingly, in electron microscopic studies, increased lysosomal response was found especially in astrocytes but also in oligodendrocytes. In astrocytes the number of heterolysosomes was conspicously increased and they were seen both in the perikaryon and in the cell processes. Such lysosomes often contained myelin-like membrane material. The presence of foreign phagocytizing cells could not be demonstrated except around the blood vessels. Furthermore, it appeared that myelin layers were not phagocytized by direct peeling process. These studies, suggest that early lysosomal changes occur in MS white matter and that such changes are mainly due to the phagocytosis of myelin inside astrocyte lysosomes. The possibility that the astrocyte response is a secondary phenomenon, which is preceded by other myelin destroying mechanisms is discussed.