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Therapeutic plasma exchange (TPE) is a well-established method of treatment for steroid-refractory relapses in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Little is known about indications and clinical responses to TPE in autoimmune encephalitis and other immune-mediated disorders of the central nervous system (CNS). We performed a retrospective chart review of patients with immune-mediated disorders of the CNS undergoing TPE at our tertiary care center between 2003 and 2015. The response to TPE within a 3- to 6-month follow-up was scored with an established rating system. We identified 40 patients including 21 patients with multiple sclerosis (MS, 52.5%), 12 with autoimmune encephalitis (AE, 30%), and 7 with other immune-mediated CNS disorders (17.5%). Among patients with AE, eight patients had definite AE (Immunolobulin G for N-methyl-D-aspartate receptor n = 4, Leucine-rich, glioma inactivated 1 n = 2, Ma 2 n = 1, and Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid n = 1). Intravenous immunoglobulins had been given prior to TPE in all but one patient with AE, and indications were dominated by acute psychosis and epileptic seizures. While TPE has a distinct place in the treatment sequence of different immune-mediated CNS disorders, we found consistent efficacy and safety. Further research should be directed toward alternative management strategies in non-responders.