Tumefactive multiple sclerosis (MS) is an aggressive form of MS that can be difficult to treat with standard therapies. In severe MS relapses, plasma exchange (PLEX) has shown some benefit, but reports of its use in patients with tumefactive MS are limited. This article describes the successful use of PLEX in a patient with tumefactive MS. A 46-year-old right-handed woman with a recent diagnosis of MS presented with drowsiness, dysarthria, horizontal nystagmus, and quadriparesis. Her brain magnetic resonance images demonstrated multiple tumefactive demyelinating lesions in the medulla, bilateral periventricular white matter, and corona radiata white matter. She was initially treated with a 10-day course of intravenous methylprednisolone without benefit; therefore, PLEX was initiated. After the second exchange, the patient started to improve and was discharged initially to rehabilitation and then home. She was started on disease-modifying therapy with natalizumab and did not experience further relapses but had slow clinical decline during the next year, which led to discontinuation of natalizumab treatment. PLEX may be used as second-line treatment in corticosteroid-resistant MS relapses, but there are limited reports of its use in patients with tumefactive MS. This patient presented with aggressive disease with multiple tumefactive lesions and did not respond to standard treatment with corticosteroids. PLEX was successful in improving her symptoms, allowing her to return home, although the disease progressed during the next year.