BACKGROUND: Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD) requires lifelong immunosuppression to prevent relapses and disability. However, long-term treatment can increase the risk of severe and opportunistic infections, which can lead to hospitalisation and death. OBJECTIVES: To describe severe infections in AQP4-IgG NMOSD, their outcomes and risk factors, to inform safer long-term management. METHODS: We retrospectively analysed prospectively collected data from 209 patients with AQP4-IgG NMOSD treated with immunosuppressive therapies and followed ⩾1 year at a UK national specialist service. Severe infections were defined as requiring intravenous therapy or hospitalisation. Predictors were identified using multivariate regression. RESULTS: Forty-nine severe/opportunistic infections occurred in 37 patients (18%), accounting for one-third of deaths (10/30). Independent predictors were longer disease duration (OR 1.10, 95% CI 1.01-1.21), older age at onset (OR 1.04, 95% CI 1.00-1.08), comorbid autoimmune disease (OR 3.91, 95% CI 1.95-7.84) and diabetes mellitus (OR 7.48, 95% CI 2.24-24.98). Four patients died after their first infection. Among survivors, nine developed recurrent infections, six of whom died. CONCLUSIONS: Severe infections can be a complication of immunosuppression in NMOSD, especially in older patients and those with comorbidities. Risk stratification, comorbidity management and infection prevention should guide therapy to balance safety and relapse control.