SARS-CoV-2 infection has been associated with several neurological disorders including encephalitis, stroke, demyelinating disorders. We report three patients with multiple sclerosis (MS) onset or with a relapse of MS, temporally correlated with SARS-CoV-2 infection. We hypothesize that SARS-CoV-2 infection, as previously reported for other viruses, could drive active inflammatory response that can contribute either to the onset of MS or its relapse. We tested anti-SARS-CoV-2 Spike Ags IgG and IgM and a cerebrospinal fluid (CSF) PCR for SARS-CoV 2. Patients underwent also to brain and spinal cord magnetic resonance imaging (MRI). In patients with MS onset, we also performed lumbar puncture, autoimmunity testing, virological screening and multimodal evoked potentials (EPs). Two patients tested negative for SARS-CoV-2 PCR in CSF, while three tested positive for anti-SARS-CoV-2 Spike Ags IgG, and negative IgM, supporting recent infection. The MRI performed in two patients with MS onset, showed widespread bilateral subcortical and periventricular active lesions and cervical lesions. MRI performed in MS relapse, showed diffuse encephalic new lesions with contrast enhancement. EPs, virological and immunity testing resulted normal. Viral infections are possible factors associated to MS pathologic mechanisms or triggers for MS. Extracellular vesicles are involved in cell-to-cell communication, also in blood-brain barrier (BBB) and macrovesicles (MVs) and exosomes in viral infection and antiviral response. Exosomes in SARS-CoV-2 infection, transfer ACE2 receptor to cells, supporting virus internalization. MVs promote BBB damage through co-involvement of tumor necrosis factor-α and interleukin-6. Resulting therefore, plausible that SARS-Cov2 infection could drive the inflammatory response causing demyelinating disease.