Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are associated with reduced Health Related Quality of Life (HRQOL). To the best of our knowledge, change of HRQOL in patients with NMOSD has not been yet measure in Iran. The objective of this study was to assess HRQOL in NMOSD and MS patients and identify related factors A cross sectional study of 41 patients with NMOSD and 136 age and sex-match MS patients was performed. A series of questionnaires including Persian validated questionnaires on HRQOL (SF-36), fatigue (MFIS), depression (BDI-II), anxiety (HAM-A) and sleep quality (PSQI) were record. All demographic variables, socioeconomic status and clinical data were also obtained. Student's T test and Mann–Whitney U test used to compare variables between groups and multivariate regression analysis applied to assay predictor factors. The mean scores of mental (MCS) and physical (PCS) components of QOL were statistically lower in patients with NMOSD compare with MS patients (β = −4.49, P = 0.004; β = −3.52, P = 0.015). Multivariate analysis indicated fatigue, depression and anxiety were independent, significant predictor of MCS (β = −0.229, P = 0.002; β = −0.229, P = 0.002; β = −0.258, P = 0.020 respectively). However, PCS was significantly predicted by fatigue (β = −0.258 P < 0.001), solely. These findings indicate NMOSD patients have lower HRQOL in compare to patients with MS. Also, screening and treatment of fatigue as the most important predictor for HRQOL is necessary. •Revise highlights to: NMOSD Patients have worse quality of life in comparison to MS patients.•NMOSD patients can be screened for fatigue, depression, and related impaired abilities with better rehabilitation strategies Fatigue is the most important variable to predict quality of life in NMOSD patients.•Healthcare policymakers in Iran and other countries should make better health and welfare service policies for NMOSD patients.