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Objectives Neuropsychiatric SLE (NPSLE) lacks evidence-based treatment strategies. This study compared the effectiveness and safety profiles of obinutuzumab (OBZ) and rituximab (RTX) in patients with NPSLE.Methods Patients with new-onset NPSLE meeting British Isles Lupus Assessment Group grade A criteria who received either OBZ or RTX between 2018 and 2024 at Renji Hospital, Shanghai Jiao Tong University School of Medicine (with ≥12 months follow-up) were included. Propensity score matching (1:2 ratio) based on age, sex and SLE Disease Activity Index (SLEDAI) was performed. The primary outcome was complete or partial response at 12 months. Kaplan-Meier curves compared therapeutic effectiveness. Safety profiles of OBZ and RTX were recorded.Results 27 patients with new-onset NPSLE were included in this retrospective study, with 9 patients receiving OBZ and 18 patients receiving RTX. At 12 months, the primary outcome was achieved in 8 of 9 patients in the OBZ group and 13 of 18 patients in the RTX group (88.9% vs 72.2%; OR: 3.08, 95% CI 0.30 to 31.33; p=0.34). Compared with the RTX group, the OBZ group demonstrated higher lupus low disease activity state attainment (74.1% vs 52.3%; p=0.049), lower SLEDAI-2000 Scores (median (IQR): 2 (1–2) vs 4 (2–4.25); p=0.04) and a trend towards higher B cell depletion rates at 12 months (57.1% vs 20.0%; p=0.08). OBZ treatment significantly shortened hospitalisation by 7 days (14.7±5.4 vs 21.9±11.9 days; p=0.04) and achieved a deeper B cell depletion at 6 months (median CD19+B cells: 0.4 (0–1.4) vs 3.5 (2–19.3) cells/µL; p=0.01), compared with the RTX group. Safety profiles were comparable between groups, with both treatments well tolerated. No deaths occurred.Conclusion These findings suggest OBZ may induce superior clinical responses in NPSLE through enhanced B cell depletion, with acceptable safety at 12 months, calling for further exploration.