Acute disseminated encephalomyelitis (ADEM) is a demyelinating central nervous system disease that is associated with high morbidity and mortality. Although the recognition of ADEM may be facilitated by newer imaging techniques, the optimal treatment of this disease remains uncertain. We describe 4 patients with severe ADEM who responded to treatment that included intensive plasmapheresis. Two of the patients were in coma at the time that plasmapheresis was instituted, and all 4 patients made an excellent recovery. Immunologic studies revealed increased serum IgA levels, increased circulating immune complex levels as measured by the Raji cell assay, and decreased numbers of T and B cells prior to treatment of ADEM. These abnormalities improved following plasma exchange. Plasmapheresis appears to be effective in reversing the neuropathologic process in ADEM. The role of this treatment modality in ADEM requires further evaluation in controlled clinical trials.