Although both multiple sclerosis (MS) and neuromyelitis optica (NMO) are demyelinating diseases, their psychiatric disturbances may differ given differences in the neurological manifestations. We used subjective and objective measurements to compare the psychiatric disturbances in patients with MS and NMO.Psychiatric disturbances were assessed in 24 MS and 35 NMO patients using the Beck Hopelessness Scale, Symptom Checklist-95 and the brief version of World Health Organization Quality of Life. Personality was assessed using the Big Five Inventory-10. Disease-related function was assessed using the Fatigue Severity Scale, Short-Form McGill Pain Questionnaire, and the Global Assessment of Function. Positivity offset (PO) and negativity bias (NB) and heart rate variability (HRV) were measured using a modified implicit affect test and photoplethysmograph, respectively. Data were analyzed using analysis of covariance with age and sex as covariates.MS patients had higher levels of depression, anxiety, panic attacks, obsessive-compulsiveness, aggression, paranoia, interpersonal sensitivity, self-regulation problems, stress vulnerability, and lower psychological quality of life (QOL) compared with NMO patients. The PO and NB and HRV values were not significantly different between groups. However, NMO patients had lower QOL, and higher levels of hopelessness, suicidality, and fatigue than the normal range. Disease duration was associated with hopelessness in NMO patients and with several psychiatric disturbances, but not hopelessness, in MS patients.Subjective psychiatric disturbances were more severe in patients with MS than in those with NMO, whereas PO and NB and HRV in patients with NMO were comparable with those of MS patients. Our findings highlight the need for different clinical approaches to assess and treat psychiatric disturbances in patients with MS and NMO.