Objective: To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS). Design: Retrospective, cross-sectional cohort study. Setting: Academic MS center. Patients: Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort. Main Outcome Measures: Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire. Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated. Results: Current pain was morecommonin subjects with NMO (n = 29) vs MS (n = 66) (86.2% vs 40.9%; P < .001) and more severe on a 10-point scale (5.38 vs 1.85; P < .001). Pain remained more common after controlling for disability and number of spinal cord segments (P =.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS (75.9% vs 37.8%; P < .001), often requiring more than 1 medication (65.5% vs 15.2%; P < .001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P =.006). Conclusions: Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.