BACKGROUND Demyelinating plaques may induce headache through disruption of the pathways, which are implicated in the pathogeneses of migraine. We report a case of 25-year-old female patient, who presented with status migrainosus fulfilling the criteria of international classification of headache disorder. She was eventually diagnosed with multiple sclerosis (MS) after an extensive work-up and long-term clinical and radiological follow-up. RESULTS At the onset of status migrainosus, magnetic resonance imaging (MRI) revealed the presence of several demyelinating lesions fulfilling Swanton criteria. She was started on migraine prophylactic treatment but there was no subsequent response. One year later, she presented with recurrent status migrainosus and a follow-up MRI revealed multiple gadolinium-enhancing lesions in the brain. She was treated with abortive migraine medications. Within the following 2 year, she developed ascending parasthesia and weakness of both lower limbs indicative of incomplete transverse myelitis in association with recurrent status migrainosus. A diagnosis of MS was established based on a follow-up MRI that satisfied the revised 2010 McDonald criteria. Both the headache and neurological signs improved with IV methylprednisolone therapy. Her headache entered remission after initiation of a disease modifying therapy. CONCLUSIONS Status migrainosus can be the initial presentation of MS. Unresponsiveness to migraine prophylactic therapy in the presence of active demyelinating plaque in MRI brain may pose a diagnostic challenge and a diagnosis of MS might be considered.