Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, while multiple sclerosis (MS) is a prevalent chronic inflammatory demyelinating disease of the central nervous system. The coexistence of these two conditions is rare. Thus, patients with NF1 may exhibit signal abnormalities on brain imaging, referred to as focal areas of signal intensity (FASI), which can mimic lesions seen in MS and complicate the differential diagnosis. We present the case of a female patient suffering from progressive paraparesis, accompanied by urinary disorders and coordination disorders of the upper limbs. Neurological examination revealed a pyramidal syndrome and a cerebellar syndrome, with an Expanded Disability Status Scale (EDSS) score of 7.5. Additionally, the skin examination showed multiple café-au-lait spots larger than 15 mm and numerous diffuse neurofibromas. Brain magnetic resonance imaging showed white matter lesions typical of MS, and isoelectrofocalization of cerebrospinal fluid proteins revealed positive oligoclonal bands. The diagnosis was primary progressive multiple sclerosis associated with neurofibromatosis type 1. The aim of this case report is to document the association of these two conditions and discuss the challenges in differential diagnosis and treatment, as early diagnosis of MS is crucial to prevent further disability in patients with NF1.