Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is a severe autoimmune disorder with high morbidity and mortality. Current treatments have limitations including relapse, highlighting the need for effective maintenance therapy. This study evaluates the efficacy and safety of mycophenolate mofetil (MMF) as long-term adjunctive therapy to first-line treatment in newly diagnosed patients with NMDARE.We conducted a prospective, randomised, open-label trial in four academic centres in China. Patients aged 14 and older with acute NMDARE, who received first-line treatments within 2 weeks of presentation to the hospital and had a modified Rankin scale (mRS) score of 2 or more, were recruited. Participants were randomly assigned to receive first-line treatment with or without MMF (0.5 g two times per day for 24 months). Primary outcomes included relapse rates and time to relapse, with secondary outcomes including cognitive deficits, treatment response (the proportion of patients with≥1 point improvement in mRS within 4 weeks) and adverse events (AEs).Of 100 patients (52% female; median age 27), those in the MMF group had fewer relapses (5.9% vs 26.5%; p=0.006) and better treatment response (84.3% vs 65.3%; p=0.03). No significant difference was found in long-term functional prognosis at 12 and 24 months. However, MMF patients had less fatigue, cognitive impairment, depression and seizures. AEs were mild-to-moderate, with no deaths or anaphylactic reactions.This study provides Class II evidence that long-term adjunctive treatment of MMF to first-line treatment of NMDARE resulted in a lower risk of relapse and was well tolerated beyond the 24 months of treatment.ChiCTR2100044362.© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.