Background: Inebilizumab is a humanized, affinity-optimized, anti-CD19 monoclonal antibody approved in Japan, South Korea and the USA to treat neuromyelitis optica spectrum disorder (NMOSD) in adults seropositive to immunoglobulin G autoantibodies against aquaporin-4 (AQP4+). Objectives: To determine the relationship between depth of B-cell depletion after inebilizumab treatment in AQP4+ NMOSD and longitudinal reductions in disease activity and infection risk. Methods: The N-MOmentum study (NCT02200770) was an international, multicenter, double-blind, placebo (PBO)-controlled, phase 2/3 trial in 230 participants (randomized 3:1, inebilizumab 300 mg:PBO) with an open-label extension of ?2 years. The primary endpoint was time to onset of an adjudicated NMOSD attack. Secondary endpoints included worsening of Expanded Disability Status Scale (EDSS) score and NMOSD-related inpatient hospitalizations. Peripheral blood B-cell counts were determined using high-resolution flow cytometry (lower limit of quantification, 0.2 cells/?L) throughout the study and correlated with clinical metrics. Results: Inebilizumab induced rapid B-cell depletion; 126/186 participants (68%) had B-cell counts ?4 cells/µL after the first dosing interval (week [W]28); the remainder had >4 cells/µL, but well below the lower limit of normal. Immediate clinical benefits versus PBO were seen in both groups; however, participants with ?4 cells/µL had greater improvements in metrics of disease activity than those with >4 cells/µL (rate/year [95% confidence interval] ?4 vs >4 cells/µL: annualized attack rate [AAR], 0.04 [0.020.07] vs 0.09 [0.050.17]; new T2 lesions, 0.51 [0.400.67] vs 1.38 [0.971.98]; EDSS worsening, 0.07 [0.050.12] vs 0.15 [0.080.26]; hospitalizations, 0.08 [0.040.14] vs 0.19 [0.090.4]). Long-term (>2.5 years) inebilizumab treatment provided sustained B-cell depletion and decreased metrics of disease activity in all participants, with significant reductions in AAR, reductions in EDSS score worsening and fewer hospitalizations regardless of depth of depletion after W28. Neither the depth of B-cell depletion after W28 nor long-term inebilizumab treatment correlated with risk of infection. Conclusions: Inebilizumab provides rapid, durable B-cell depletion in participants with NMOSD. These findings suggest that deep, sustained B-cell depletion is beneficial in NMOSD; thus, monitoring B-cell counts may be informative, especially in the first 2.5 years of inebilizumab treatment.