Background: Since the beginning of the COVID-19 pandemic and development of new vaccines, the issue of post-vaccination exacerbation or manifestation of demyelinating central nervous system (CNS) disorders has gained increasing attention. Case presentation: We present a case of a 68-year-old woman previously diagnosed with multiple sclerosis (MS) since the 1980s who suffered a rapidly progressive severe sensorimotor paraparesis with loss of bladder and bowel control due to an acute longitudinal extensive transverse myelitis (LETM) after immunization with the mRNA Pfizer–BioNTech COVID-19 vaccine. Detection of Aquaporin-4-antibodies (AQP4) in both serum and CSF led to diagnosis of AQP4-antibody positive neuromyelitis optica spectrum disorder (NMOSD). Treatment with intravenous corticosteroids and plasmapheresis led to a slight improvement of the patient’s symptoms. Conclusions: Pathogenic mechanisms of post-vaccination occurrence of NMOSD are still unknown. However, cases like this should make aware of rare neurological disorders manifesting after vaccination and potentially contribute to improvement of management of vaccinating patients with inflammatory CNS disorders in the future. So far two cases of AQP4-antibody positive NMOSD have been reported in association with viral vector COVID-19 vaccines. To our knowledge, we report the first case of AQP4-antibody positive NMOSD after immunization with an mRNA COVID-19-vaccine.