Abstract: Objective：To investigate the clinical characteristics of Hashimoto’s encephalopathy (HE) and explore the treatment of glucocorticoid unresponsive HE. Methods：Six cases with HE were collected in Changhai Hospital, Navy Military Medical University from December 2012 to January 2018. The clinical characteristics were observed, and each patients was given glucocorticoid therapy after diagnosis. This was the first attempt to treat HE with double filtration plasmapheresis (DFPP) in patient presenting unresponsive to methylprednisolone therapy. Results：Cognitive dysfunction was the most common clinical manifestation (6/6). All cases had increased serum antithyroid antibodies. All patients were treated with regular methylprednisolone therapy. Among these patients, 2 cases were ineffective. A 59-year-old male patient manifested cognitive dysfunction, seizure attacks, who was unresponsive to methylprednisolone therapy, and the disease continues to progress. Brain MRI scan showed significant diffused abnormal signals on bilateral thalamus, cerebral peduncles, and superior cerebellar peduncles. After 3 sessions of DFPP, his clinical symptoms improved rapidly and significantly, and MRI results showed that his brain lesions disappeared finally. In one-year follow-up visiting, it did not show recurrence and his neurological function kept good. Conclusions：Although most HE cases have been highly responsive to glucocorticoid treatment, a few patients are resistant to the therapy. For those who are resistant or contraindicative to steroids treatment, DFPP may be an alternative choice.