Investigators reported final safety and efficacy data from the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), in which patients aged 18 and older who had an Expanded Disability Status Scale score of less than or equal to 8 and a recent history of attacks were randomized 3:1 to inebilizumab or placebo monotherapy for 28 weeks or up to attack occurrence (the randomized controlled period; RCP). The primary outcome was time to adjudicated attack, at which point patients could enter the inebilizumab open-label period (OLP). Among 230 participants randomly assigned and treated, 216 (93.9%) entered and 174 (80.6%) finished the OLP. In the RCP, 87.0% were free from attacks with inebilizumab versus 59.9% with placebo (72.8% risk reduction, P<.001). In the OLP, 87.7% of those who remained on inebilizumab were attack-free compared with 83.4% of those switched from placebo. Total exposure was 730.36 person-years with an annualized attack rate of 0.092; 63.5% of attacks happened in the first year. Treatment-emergent adverse events were reported by 39.6% of participants, with urinary tract infections (26.2%), nasopharyngitis (20.9%), and arthralgia (17.3%) occurring most frequently. Infusion-related reactions with inebilizumab occurred in 12.9% of participants and 105 had transient low IgG (<700 mg/dL) during treatment, but no associations were observed between the worst IgG, IgM, or IgA levels and the incidence of any infection or an infection equal to or greater than grade 3 (Fisher exact test, all P>0.05). Three participants died, including one from complications of an NMOSD attack, one from a central nervous system event of unclear etiology, and one from COVID-19, after 9, 224 and 1,225 days of inebilizmab treatment, respectively. During 5.5 years, the N-MOmentum trial demonstrated a sustained low risk of attack among participants receiving inebilizumab, with no evidence of unexpected serious adverse events, including serious infection.