Background: Long-term use of B-cell depleting monoclonal antibodies is associated with reduced immunoglobulin (Ig) levels that can predispose to infection. The randomized, placebo-controlled N-MOmentum trial of the anti-CD19 B-cell depleting monoclonal antibody inebilizumab enrolled and dosed 230 participants with neuromyelitis optica spectrum disorder (NMOSD). The association between long-term immunoglobulin levels and infection rates was assessed in both the randomized controlled phase (RCP) and open-label period (OLP; minimum 2 years) of N-MOmentum. Objectives: To evaluate long-term changes in Ig levels and infection rates in participants treated with inebilizumab. Methods: Ig levels were measured systematically by a central clinical laboratory. Adverse events, including infections, were collected and recorded. Opportunistic infections were predefined based on medical review. Results: Ig levels were analyzed for 174/230 enrolled participants who were given inebilizumab for 4.75 years post-baseline. Ig levels decreased with inebilizumab; the mean decrease in total Ig at 4.75 years was 35%. The mean percent change from baseline through 4.75 years was 62% for IgM, 50% for IgA and 30% for IgG. During the RCP, the rate of infection per 100 person-years was 140.2 (97.1, 195.9) for participants on placebo and 138.1 (113.9, 165.9) for those on inebilizumab. Infection rates per 100 person-years were lower in the OLP than the RCP: year 2: 69.9, year 3: 61.5, and year 4: 62.3 (614.6 person years of follow-up). The most common infections seen were nasopharyngitis, upper respiratory tract infection, urinary tract infection, bronchitis and influenza. The proportion of participants with an infection was similar for participants with IgG levels below and above the lower limit of normal (78.9% vs. 72.9%). An IgG level below 300 mg/dL was observed at least once in 8 participants, but the proportion of participants with infection did not differ between those with IgG <300 mg/dL and those with IgG ?700 mg/dL (75.0% vs. 72.9%). Conclusions: As expected, immunoglobulin levels decline with continued inebilizumab use. However, the rate of infections did not increase with continued inebilizumab use and infection rates were similar between study participants with normal and low IgG levels in this cohort.