Rationale:Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple systems. Central nervous system (CNS) demyelinating syndromes are one of the rare neurological manifestations of SLE, whose diagnosis, treatment, and prognosis are rarely reported. Belimumab, an anti-BAFF monoclonal antibody, has been approved by the FDA for the treatment of SLE. We aimed to assess the effects of belimumab on demyelinating syndromes in patients with SLE.Patient concerns:Six patients with demyelination in SLE who were managed at Traditional Chinese and Western Medicine Hospital of Wuhan from March 2021 to March 2023, who received belimumab ≥ 5 times, were enrolled. Ten age- and sex-matched SLE patients with noutneuropsychiatric systemic lupus erythematosus (NPSLE) and normal controls were recruited to analyze potential biomarkers.Diagnoses:All patients were diagnosed with SLE based on the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria or the 2019 EULAR/ACR classification criteria. All SLE patients with CNS demyelinating syndromes were diagnosed by rheumatologists, neurologists, and radiologists.Interventions:These patients were administered belimumab combined with standard treatment (glucocorticoids and/or antimalarials and/or immunosuppressants [cyclophosphamide, mycophenolate, methotrexate, etc.]).Outcomes:Six patients were included in the study (100% female, mean [range] age at first demyelinating episode 42.8 [24–66] years). The most common extra-CNS features in these patients were rash, arthritis, alopecia, leukopenia, and hypocomplementemia. After Belimumab treatment, 3 of 6 (50%) patients achieved complete remission with decreased prednisone, 2 improvements, and 1 relapsed with uterine surgery. Compared with the baseline, 3.5 months post belimumab treatment, the disease activity score SLEDAI (21.5–5.5,P< .001), C3 and C4 increased, and extra-CNS symptoms improved rapidly. Moreover, The expression of lupus susceptibility gene PBX1 in CD19+ B cells was lowest in demyelinating syndromes with lupus patients compared with healthy volunteers and lupus patients without demyelination, and its relative expression negatively correlated with SLE disease activity.Conclusion:Belimumab could be an effective and safe option for the treatment of SLE demyelination. In addition, PBX1 might be a potential biomarker for the clinical diagnosis of lupus in patients with demyelinating syndrome.