Objectives: To assess loss of employment, work hours, and wages of people with aquaporin-4 antibody-positive or double-seronegative/antibody status unknown neuromyelitis optica spectrum disorder (NMOSD) internationally. Methods: An investigator-designed survey was administered to adults ages 18–70 years with NMOSD and distributed by neurologists in 23 countries, July 2022 to September 2023. Results: There were 897 participants (635 aquaporin-4 antibody positive, 262 double-seronegative/untested; 81.4% female, average age 42.5 years, average disease duration 7.6 years, median 2 disease attacks since diagnosis). NMOSD impact was visual loss (34.0% unilateral; 28.2% bilateral), 61.8% with spinal cord disease, 55.6% with pain, 43.6% with fatigue, 38.2% with depressed mood, and 25.0% with gait aid use. In total, 92.6% took immunosuppressive therapy. Employment rates were 62.6% before and 36.3% after NMOSD diagnosis. In a multivariable model, statistically significant independent associations with unemployment in NMOSD were older age (odds ratio (OR) = 0.97, p < 0.001), being female (OR = 0.48, p < 0.001), bilateral visual loss (OR = 0.61, p = 0.02), highest frequency of depressed mood (OR = 0.29, p < 0.001), and walking aid use (OR = 0.38, p < 0.001). Discussion: Approximately 1/3 of people living with NMOSD of potential working age are in the workforce. Unemployment in NMOSD is associated with previously recognized factors but also self-reported low mood, gait aid use, and bilateral visual loss. © The Author(s), 2025. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).