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To evaluate the long-term effects of rituximab (RTX) on total and specific immunoglobulins (Igs) in patients with neuromyelitis optica spectrum disorders (NMOSDs).Total IgG, IgA, and IgM levels were evaluated in 15 patients with NMOSDs treated with RTX (median follow-up 70 months). Anti-aquaporin 4 (AQP4)-IgG titration was performed on samples from 9 positive patients. Anti-tetanus (TET), anti-varicella-zoster virus (VZV), and anti-Epstein–Barr virus nuclear antigen (EBNA) IgGs were also tested in patients with NMOSDs and in 6 healthy controls (HCs).RTX reduced total IgG by 0.42 g/L per year, IgA by 0.08 g/L per year, and IgM by 0.07 g/L per year. Hypogammaglobulinemia (hypo-IgG) (IgG < 7 g/L) developed in 11/15 patients. Severe hypo-IgG (IgG < 4 g/L) was found in 3/15 patients, of whom 2 patients developed serious infectious complications. In group analysis, anti-AQP4 IgG titers were reduced by RTX over time, and a significant correlation between anti-AQP4 IgG titers and total IgG levels was found. The effects of RTX were observed on pathogen-specific IgGs as well. In particular, the levels of anti-TET IgG in patients were significantly lower than those in HCs. The half-life of anti-TET IgG was reduced by about 50% in patients compared with the general population.Long-term RTX treatment is associated with the risk of hypo-Ig and reduction of anti-TET protection in patients with NMOSDs. Results obtained in this study suggest the importance of monitoring total and specific Ig levels before and during treatment with anti-CD20 drugs to prevent hypo-Ig–related complications and to optimize clinical management.