Introduction <p>To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of obinutuzumab β, a novel glycoengineered type II anti-CD20 monoclonal antibody, in patients with neuromyelitis optica spectrum disorder (NMOSD).</p> Methods <p>In this multicenter, open-label, single-arm, phase Ib trial (NCT05314010), 11 aquaporin protein-4 (AQP4)-IgG-positive patients with NMOSD received obinutuzumab <i>β</i> at 500 mg or 1000 mg on days 1 of weeks 1 and 3. Patients in the 500-mg group could escalate to 1000 mg after 24 weeks if tolerated. Evaluations occurred at specified weeks (24–208), with 1000-mg doses on days 1 of weeks 25, 27, and every 26 weeks thereafter in patients who are relapse-free. Safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity were assessed.</p> Results <p>All participants with 500 mg (<i>n</i> = 3) transitioned to 1000 mg after 24 weeks. During the entire study period, all 11 participants experienced at least one treatment-emergent adverse event (TEAE); 90.9% had treatment-related adverse events (TRAEs). Serious adverse events were reported in 54.5%, with 27.3% related to obinutuzumab β. No TEAEs or TRAEs led to treatment discontinuation, withdrawal, or death. Two patients had early relapses on days 26 and 27 post-first dose, respectively; one withdrew immediately, while the other remained on treatment for 1 year. The 2-year disease relapse-free rate was 81.8% [95% confidence interval (CI): 44.7%, 95.1%], and the annualized relapse rate (ARR) declined from 1.3 before 2-year treatment to 0.2 (95% CI: 0.1, 0.2) after obinutuzumab β, representing an 87.7% reduction.</p> Conclusion <p>Obinutuzumab <i>β</i> demonstrated manageable safety and may have promising efficacy against NMOSD. Despite the lack of a comparator group, the results support evaluation in phase III trials.</p> Clinical trial registration <p><a href="https://clinicaltrials.gov/">https://clinicaltrials.gov/</a> (#NCT05314010).</p>