The neuroradiological evidence of a single, large white matter lesion with mass effect, clinically revealed by signs of endocranial hypertension, is highly suspicious for central nervous system neoplasm. In rare cases, a demyelinating disorder can start with atypical features suggestive of a brain tumor; in these cases a brain biopsy is often carried out. We report our experience regarding cases of multiple sclerosis (MS) with atypical tumor-like presentation. None of our patients underwent biopsy. Serial magnetic resonance imaging performed during steroid treatment, together with other paraclinical data, were sufficient for the final diagnosis of MS. These cases are characterized by a severe clinical course and a rapid clinical deterioration, only partially modified by medical treatments. Atypical severe cases, misdiagnosed as MS, can be indeed due to primary CNS vasculitis.