The objective of the present study was to assess the efficacy of therapeutic plasma exchange (TPE) in patients with severe refractory anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis. Patients with severe anti-NMDA receptor encephalitis who showed no improvement after steroids and/or intravenous immunoglobulin treatment for at least 10?days were enrolled. All patients received immunotherapy and were divided into a TPE group and a non-TPE group according to treatment received. Each patient in the TPE group received at least 1 TPE course. NMDA receptor antibody titers in the cerebrospinal fluid (CSF) and plasma were evaluated within 1?week after the last TPE procedure. The clinical efficacy of treatment was evaluated after 1?month, 2?months, 3?months, 6?months, and 12?months. Forty patients were enrolled: 19 in the TPE group and 21 in the non-TPE group. Nineteen patients received TPE for a total of 118 procedures. NMDA receptor antibody titers in the CSF and/or plasma decreased or were negative after the last TPE procedure in 18 patients (94.7%). Compared with the non-TPE group, the TPE group exhibited greater clinical improvement after 1?month and 2?months following treatment (P < 0.05). After 3?months, 6?months, and 12?months, there were no significant differences in the outcomes between the TPE group and non-TPE group. The results suggest that TPE might rapidly improve the clinical manifestations in patients with severe refractory anti-NMDA receptor encephalitis, and we believe that TPE should be considered as a first-line treatment. ? 2019, The American Society for Experimental NeuroTherapeutics, Inc.