Seronegative neuromyelitis optica spectrum disorder (NMOSD) is a diagnostic challenge. This study aimed to characterize misapplication of the 2015 international criteria for seronegative NMOSD. We reviewed 35 consecutive seronegative NMOSD referrals to a tertiary center. Two (6%) met formal criteria, and 2 (6%) were clinically suspected of NMOSD without fulfilling radiologic supportive criteria. Alternative diagnoses were common including multiple sclerosis (37%), optic neuritis (14%), functional neurologic disorder (11%), and other (38%). Immunosuppression with rituximab was used in 3 of 4 patients with functional neurologic disorder. Misapplication of the 2015 criteria is common, and alternative explanations in seronegative NMOSD patients should be strongly considered.