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We aimed to evaluate the mortality of patients with AQP4 antibody-seropositive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) in Denmark compared with that in the general population./r/nWe identified patients with AQP4-Ab+ NMOSD fulfilling the 2015 International Panel for Neuromyelitis Optica Diagnosis (IPND) criteria from multiple sources (laboratories and the Danish Multiple Sclerosis Registry). We obtained detailed information about patients from hospital records and about the general population matched on age, sex, and calendar year from Statistics Denmark. We calculated standardized mortality ratio (SMR), excess number of deaths per 1,000 person-years (EDR), and life expectancies compared with those of the matched general population. We examined predictive factors of mortality and the cause of death./r/nOf 66 patients with AQP4-Ab+ NMOSD between 2008 and 2020, 15 died. Overall, the SMR was 2.54 (95% CI 1.47-4.09), and the EDR was 16.8 (95% CI 4.6-34.3). The median life expectancy for patients with AQP4-Ab+ NMOSD was 64.08 years (95% CI 53.02-83.9), compared with 83.07 years for the general population. Risk of death over time was increased in the patient population with a hazard ratio (HR) of 2.22 (1.34-3.68; = 0.002). The cause of death was directly related to NMOSD in 93% of the cases. The age at disease onset was an independent predictor of death (HR 1.042; 95% CI 1.006-1.079; = 0.02)./r/nAQP4-Ab+ NMOSD is associated with increased mortality and shorter life expectancy compared with that in the general population, underlining the need for highly effective treatment approaches.