Balò's concentric sclerosis (BCS) is considered a rare demyelinating disease and regarded as an aggressive variant of multiple sclerosis (MS). We describe three cases (one male and two females) with neuroimaging features suggestive of BCS and heterogeneous symptoms, with benign long-term clinical course upon treatment with natalizumab and fingolimod. Neurological examination, blood and cerebrospinal fluid analyses, brain and spinal cord magnetic resonance imaging (MRI) and brain proton magnetic resonance spectroscopy were performed. At onset, patient #1 showed predominant cognitive impairment with consciousness disturbances; patient #2 presented with left hemiparesis; patient #3 demonstrated hesitance in speech and in written word production, along with right central facial palsy. All patients showed the typical MRI changes associated with BCS, such as concentric rings or a whorled appearance on T2-weighted and contrast-enhanced T1-weighted images. They were treated with high dosage i.v. steroid with clinical improvement and followed-up for 3 years with different clinical course. Two patients fulfilled the revised McDonald criteria for MS and received preventive therapy, natalizumab and fingolimod, respectively, whereas the third patient is still stable without clinical and radiological evolution. All of them did not have new exacerbations or MRI lesions over 2-4 year follow-up. Our descriptions demonstrate the heterogeneity of clinical presentation of BCS. Moreover, these case reports suggest that BCS may neither be rapidly progressive nor fatal and may be considered part of the MS spectrum. In line with this hypothesis, current treatments for MS were effective in our patients.