Autoimmune encephalitis (AE) is a kind of encephalitis mediated by the autoimmune response. There is no uniform standard for immunotherapy of this disease, especially for failure of first-line immunotherapy or recurrent AE. Here, we report the case data of patients with failure of first-line immunotherapy or recurrent AE who were treated with ofatumumab (OFA).We retrospectively analyzed 18 patients with failure of first-line immunotherapy or recurrent adverse events treated with OFA. We collected general information, clinical manifestations, auxiliary examinations, treatment and prognosis, and adverse reactions. A retrospective analysis was conducted on these data, and the results were discussed in conjunction with a review of the relevant literature.Among the 18 patients treated with OFA, significant improvements were observed in psychiatric symptoms (p = 0.005) and seizure frequency (p = 0.002). The CD20+ B cell levels declined most rapidly within the first week after the initial OFA injection and reached their lowest point at 1 month post-treatment. However, as the interval between doses increased, CD20+ B cell levels rebounded. In some patients who received repeated injections, CD20+ B cell levels were further reduced and maintained at a lower level. Both the modified Rankin Scale (mRS) and Clinical Assessment Scale for Autoimmune Encephalitis (CASE) scores showed statistically significant improvement post-OFA treatment (p < 0.01).Clinical data indicate that OFA demonstrates therapeutic efficacy in failure of first-line immunotherapy or recurrent AE, as evidenced by improved symptom control, decreased relapse rates, and an acceptable safety profile. However, this study is retrospective, and the clinical sample size is small, which may be biased. In the follow-up study, we will further expand the scale of case collection to further prove the efficacy and prognosis of OFA in treating AE patients.Copyright © 2025 Liu, Zhang, Song, Feng, Cao and Bu.