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• Clinical onset of multiple sclerosis and myelin-oligodendrocyte-glycoprotein-antibody-associated disease has been reported in association with SARS-CoV-2-vaccination. • There is uncertainty as to whether this is causality (" denovo" disease) or temporal coincidence. • At least in our cohort, the clinical onset of MS after vaccination against SARS-CoV-2 does not indicate " denovo" development of new disease. • The first clinical manifestation of preexisting subclinical neuroinflammation is most likely to have a coincidental temporal relationship with vaccination. • The present case study is relevant for vaccination guidance and counseling of patients. Clinical onset of multiple sclerosis (MSpostvacc) and myelin-oligodendrocyte-glycoprotein-antibody-associated disease (MOGADpostvacc) has been reported in association with SARS-CoV-2-vaccination. There is uncertainty as to whether this is causality (denovo disease) or temporal coincidence (manifestation of a preexisting, subclinical neuroinflammation). Comparing the clinical characteristics of MSpostvacc-patients versus patients with MS (PwMS) whose clinical onset occurred independently of vaccination (MSreference). Consecutive patients with clinical onset ≤30 days after SARS-CoV-2-vaccination were included. Clinical data, cerebrospinal fluid (CSF) parameters and magnetic resonance imaging (MRI) as well as optical coherence tomography (OCT) data were compared to an age- and sex-matched MSreference-cohort. We identified 5 MSpostvacc and 1 MOGADpostvacc patients who developed their clinical onset ≤ 30 days after SARS-CoV-2-vaccination. Clinical characteristics, CSF, MRI and OCT parameters from MSpostvacc patients were comparable to the MSreference cohort and showed evidence of preexisting subclinical CNS disease. The single case with MOGADpostvacc clearly differed from PwMS in higher CSF cell counts, remission of MRI lesions during follow-up, and absence of oligoclonal bands. Our case series indicates that MSpostvacc patients showed a rather typical initial manifestation in temporal association with SARS-CoV-2-vaccination and harbored preexisting subclinical neuroinflammation. This argues against the denovo development of MS in this cohort. [ABSTRACT FROM AUTHOR]