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Marburg's disease (MD) is an extremely rare and aggressive form of multiple sclerosis (MS). In some cases, MD presents with tumefactive demyelinating lesions with a “tumor-like” appearance in MRI images, for which it may be difficult to achieve a form of differential diagnosis between definitive tumors or abscesses. Here we report a case of MD histopathologically confirmed after neuronavigationguided biopsy. Postoperative course was uneventful and following discharge, the patient attended outpatient follow-up appointments and received i.v. cyclophopsphamide, achieving progressive clinical remission. A nine-month follow-up brain MRI scan with gadolinium showed no signs of progressing demyelinating disease with an evident reduction of the biopsied lesion, and almost complete retrogression of the other two lesions. In our opinion, and through the analysis of currently available literature, early neuronavigation-guided biopsy is a highly recommend, valuable, and safe diagnostic tool; it is also preferable to stereotactic biopsy, since its benefits include a very low bleeding rate and brain damage risk, with minimum mortality and morbidity rates. It also allows the identification of the specific histological pattern, helping to select the best medical treatment approach and contributing to increase patient outcome and life expectancy.