Background: Neuromyelitis optica spectrum disorders (NMOSD) are neuroinflammatory diseases of the central nervous system. Patients suffer from recurring relapses and it is unclear whether relapse-independent disease activity occurs and whether this is of clinical relevance. Objective: To detect disease-specific alterations of the retinal vasculature that reflect disease activity during NMOSD. Methods: Cross-sectional analysis of 16 patients with NMOSD, 21 patients with relapsing-remitting multiple sclerosis, and 21 healthy controls using retinal optical coherence tomography (OCT), optical coherence tomography angiography (OCT-A), measurement of glial fibrillary acidic protein (GFAP) serum levels, and assessment of visual acuity. Results: Patients with NMOSD but not multiple sclerosis revealed lower foveal thickness (FT) ( p = 0.02) measures and an increase of the foveal avascular zone (FAZ) ( p = 0.02) compared to healthy controls independent to optic neuritis. Reduced FT ( p = 0.01), enlarged FAZ areas ( p = 0.0001), and vessel loss of the superficial vascular complex ( p = 0.01) were linked to higher serum GFAP levels and superficial vessel loss was associated with worse visual performance in patients with NMOSD irrespective of optic neuritis. Conclusion: Subclinical parafoveal retinal vessel loss might occur during NMOSD and might be linked to astrocyte damage and poor visual performance. OCT-A may be a tool to study subclinical disease activity during NMOSD.