Introduction: The aim of this study was to present the follow-up data of 11 patients with tumefactive demyelinating lesions (TDLs) with pointing the challenges of differential diagnosis and indicate the possible prognostic features. Methods: In our study, a retrospective analysis was performed by collecting clinical, laboratory, and radiological findings with the prospective follow-up of 11 patients with TDL who presented with at least one cerebral demyelinating lesion (>2 cm) and admitted to Haydarpasa Numune Training and Research Hospital between 2000 and 2020. Results: About 72.7% of the patients were female (n=8) and 27.2% were male (n=3). There was a female predominance (F/ M=2.66) and the mean age of onset was 33.45 years (18-68 years). While TDL was the first neurological event in 9 (81.8%) of 11 patients, 2 patients (18.1%) had developed TDL after the diagnosis of multiple sclerosis (MS). Among nine patients whose first neurological event was a tumefactive lesion, three of them were diagnosed with neuromyelitis optica, two patients with MS, and two patients with acute demyelinating encephalomyelitis. Two patients were followed up as TDL with a monophasic course. The average follow-up period was 62.16 months (1-180 months). Discussion and Conclusion: It is difficult to diagnose TDL by distinguishing it from other lesions, including brain tumors, with clinical and radiological findings. Detailed anamnesis, physical examination, and magnetic resonance imaging can eliminate the need for brain biopsy in patients for the diagnosis. Early diagnosis of TDL and aggressive immunomodulatory treatments may delay the progression to a second demyelinating event or clinically definite MS.