Abstract This report describes a rare case of neuromyelitis optica spectrum disorder (NMOSD) complicated by systemic capillary leak syndrome (SCLS) and reviews the literature to examine the clinical features, pathogenesis, and therapeutic implications of autoimmune disease–associated SCLS. A 20-year-old woman with NMOSD developed sudden-onset SCLS, presenting with hypotension, hemoconcentration (hematocrit 58.7%), hypoalbuminemia (26 g/L), and pulmonary edema after initial immunotherapy.