Athena Enderami,1 Rose Fouladi,2 Seyed Hamzeh Hosseini3 1Department of Psychiatry, School of Medicine, Mazandaran University of Medical Sciences, Mazandaran, Sari, Iran; 2Sport Injuries and Corrective Exercise, University of Mazandaran, Mazandaran, Babolsar, Iran; 3Psychiatry and Behavioral Sciences Research Center, Addiction Institute, Mazandaran University of Medical Sciences, Sari, Iran Background: Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system (CNS). MS with episode of psychosis is a rare entity, and to the best of our knowledge, no case has been reported from Iran till date. Case presentation: We report a case of MS with first-episode psychosis in a 27-year-old single man with no history of psychiatric disorder or drug abuse. The patient developed neurological symptoms after 3 months and was finally diagnosed as a case of MS. His symptoms started with behavioral dysfunctions and progressively resulted in depression. Subsequently, treatment was performed with citalopram 20 mg daily, risperidone 2 mg three times a day, and biperiden 2 mg three times a day; however, no improvements in the symptoms were observed. T2-weighted magnetic resonance imaging has demonstrated periventricular and white matter multiple sclerotic plugs with lesions. Eventually, MS was diagnosed after the appearance of paresthesia, upper and lower limb muscle weakness, ataxia, and urinary incontinency as typical signs. Then, the medications were changed to methylprednisolone and interferon therapy, which resulted in improvements in the clinical conditions of the patient. Conclusion: Based on the fact that organic disorders such as MS may sometimes appear with initial pure psychiatric symptoms without any neurological signs and symptoms, examinations for symptoms linked to CNS dysfunction, cognitive changes, atypical symptoms, detailed neurological examination, and limited response to conventional antipsychotic drugs are highly recommended to be carried out for patients with first-episode psychosis and even in the follow-up period. Keywords: multiple sclerosis, MS, episode, psychotic disorders, case report, signs, symptoms