To investigate the mode of the pathogenesis of multiple sclerosis (MS), we transferred cerebrospinal fluid (CSF) cells, predominantly mononuclear cells, from MS patients at both exacerbation and remission stages of the disease into severe combined immunodeficiency mice by intracisternal injection. As controls, (i) CSF cells from patients with cervical spondylosis and (ii) peripheral blood mononuclear cells from normal individuals were transferred. Four to 6 weeks after transfer, most mice transferred with CSF cells from MS patients at the exacerbation stage of the disease developed paralysis and ataxia. The histopathological examination on the sacrificed mice revealed multiple scattered, discrete lesions localized in the white matter of the brainstems and spinal cords. These lesions were characterized by various degrees of tissue necrosis, involving inflammatory-cell infiltration. Most infiltrating cells were macrophages, although a smaller number of granulocytes appeared in several foci. Reactive astrocytic gliosis was also seen around the necrotic foci. Furthermore, these lesions exhibited demyelination. These histopathological changes are similar to those seen in MS. In contrast, none of the severe combined immunodeficiency mice transferred with CSF cells from MS patients at the remission stage of the disease, or with CSF cells from the patients with cervical spondylosis, or with peripheral blood mononuclear cells from normal individuals showed any such histopathological changes. These observations provide convincing direct evidence of encephalitogenicity of mononuclear cells in CSF from MS patients at the exacerbation stage of the disease.