Background: The association of multiple sclerosis (MS) and neurofibromatosis type 1 (NF1) has been rarely reported. Objectives: To report a case of MS associated with NF1. Methods: Case Report. Results: An African American female patient who was diagnosed with NF1 at age 10 developed a severe, acute left-sided optic neuritis at age 21. NF1 diagnosis was based on café au lait spots, axillary freckling, subcutaneous neurofibromas, and left leg plexiform neurofibroma. Optic neuritis partly responded to a 3-day course of high dose intravenous methylprednisolone (IVMP). Magnetic resonance imaging (MRI) of the brain at optic neuritis presentation demonstrated multiple non-enhancing T2/Fluid Attenuated Inversion Recovery hyperintense lesions predominantly in periventricular white matter, corpus callosum, and left cerebellar peduncle, as well as short segment cervical spinal cord lesions at C2 and C3 levels. Cerebrospinal fluid oligoclonal immunoglobulin G bands were positive. The patient was diagnosed with MS and started on interferon beta-1a subcutaneously three times a week. She had another mild left optic neuritis at age 22, but otherwise remained neurologically stable until age 27, when she developed a new MS relapse with myelopathic symptoms associated with an increase in cervical spinal cord MRI lesion load. Following a 5-day course of high dose IVMP she recovered to her baseline. Disease modifying treatment was switched to fingolimod. At that time, anti-aquaporin-4 antibody and anti-myelin oligodendrocyte glycoprotein antibody were negative. Interval subclinical MRI signs of MS disease activity prompted further escalation of therapy to natalizumab at age 29, with good MS disease control over the following 15 months. The patients motor function remains limited by left leg weakness that may be due to a combination of central and peripheral lesions, as well as orthopedic complications of her large left leg plexiform neurofibroma that extends from pelvis to her left hip and left knee. This lesion has caused destruction of the involved joints, requiring left total hip arthroplasty and left total knee arthroplasty. She currently walks with a crutch and uses a left leg brace. Conclusions: MS can occur in patients with NF1 and should be considered in NF1 patients who develop symptoms non-typical for NF1. A potential genetic association between two conditions warrants further investigation.