Objective To investigate the therapeutic effect of double filtration plasmapheresis (DFPP) on severe anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis and its clinical significance. Methods We retrospectively analyzed the clinical data from 9 patients with severe anti-NMDAR encephalitis confirmed by Changhai Hospital of Naval Medical University (Second Military Medical University) from Jan. 2014 to Mar. 2018. The 9 patients did not respond to methylprednisolone shock therapy. We collected the clinical manifestations, and examination results of laboratory, electroencephalogram and imaging, and analyzed the therapeutic effect of DFPP. Results Nine anti-NMDAR encephalitis patients, including 5 females and 4 males, were admitted to neurology intensive care unit. Their ages were ranged from 15 to 69 years old, median age of onset was 37 years old, and average hospital stay was (33.2±7.6) d. The main clinical symptoms were mental behavioral abnormalities (9 cases), autonomic dysfunction (9 cases), seizures (7 cases), central hypopnea (5 cases), and consciousness disorders (5 cases). One patient was complicated with ovarian teratoma. Nine patients were positive for anti-NMDAR antibodies in cerebrospinal fluid, and 7 patients were positive for anti-NMDAR antibodies in serum. All the 9 patients were examined by electroencephalogram, and 7 of them had abnormal findings, mainly with diffuse changes and abnormal slow waves. Brain magnetic resonance imaging showed that abnormal signals could be seen in the frontal lobe, parietal lobe, temporal lobe, hippocampus and other brain regions of 4 patients, and no abnormal signals were found in the other 5 patients. Nine patients were treated with DFPP after ineffective treatment with methylprednisolone, 5 of them recovered completely, and the other 4 cases had significantly improved residual symptoms. Conclusion DFPP can be used as an alternative for patients with severe anti-NMDAR encephalitis who are not sensitive to glucocorticoid therapy. It has better clinical efficacy and it is not restricted by allogeneic plasma resources.