Background: Atypical demyelinations exhibit pathological characteristics similar to those observed in multiple sclerosis (MS), although their clinical manifestations and radiological patterns differ from those of classic MS. The relationship between MS and its demyelination variants is still unclear, making it difficult to identify patients at risk of developing MS. Tumefactive Demyelination associated with MS is a rare and understudied variant due to the lack of large patient cohorts. The estimated incidence is 1-2 per 1000 MS cases, although other authors suggest a prevalence of 1.4 to 8%. The most common clinical manifestations include hemiparesis or hemiplegia, and headache, aphasia, cognitive, visual, and sensory disturbances, as well as epilepsy, may also be identified. Several important aspects stand out in this aggressive form of demyelination, characterized by tumor-like lesions that are equal to or greater than 2 cm in size. These lesions can occur as single or multiple, and a biopsy may be indicated if the imaging is inconclusive. These lesions may be present in patients with diagnosed MS in 30% of cases or may present as the first episode. Objective: To analyze the cases attended with tumefactive demyelination, following up on these cases and subsequently defining the diagnosis of MS. Methods: Patients included in the database of the referral service for MS patients care between 1997 and 2019 at the Hospital da Restauração (Recife, Pernambuco) were analyzed. The inclusion criterion was the presence of clinical and imaging findings compatible with tumefactive lesions and the possibility of a final MS diagnosis. Results: Seven cases were analyzed, including six female and one male patient, with ages ranging from 11 to 42 years. The predominant signs and symptoms were headache, low visual acuity, motor deficit, seizures, and altered sensorium. MRI revealed multiple pseudotumoral lesions. Three patients underwent biopsy due to suspected primary brain tumor. All patients received pulse therapy with methylprednisolone (MTP), one underwent plasmapheresis (PLEX), three used beta-interferon, one used glatiramer acetate (GA), and two used natalizumab as a second option. The EDSS ranged from 0 to 4 at the onset and from 0 to 7 at the last evaluation, with one death recorded. Conclusion: Variants of MS have demonstrated tumefactive lesions and distinct immunological signatures. Tumefactive demyelinating lesions (TDLs) can also occur in patients with other atypical demyelinating syndromes, such as ADEM, NMOSD seropositive for AQ4 IgG or seronegative, as well as MOGAD and other neuroinflammatory diseases (neurosarcoidosis and Behçet’s disease), posing a constant challenge, especially in these cases.