A 23-year-old previously healthy man (Patient 1) and a 33-year-old woman with a past history of depression (Patient 2) developed neurological symptoms approximately 1 week after receipt of the first COVID-19 mRNA vaccination and deteriorated over the next week. Patient 1 reported nausea, headache, a high fever, and retrograde amnesia. Patient 2 reported visual disturbance, headache, dysarthria, a left forearm tremor, dysesthesia of the mouth and distal limbs, and visual agnosia. PCR test results for SARS-CoV-2 were negative. Complete blood cell count, biochemistry, and antibody test and cerebrospinal fluid test findings were unremarkable. Diffusion-weighted and fluid-attenuated inversion recovery MRI of the brain showed a high signal intensity lesion at the midline of the splenium of the corpus callosum compatible with cytotoxic lesions of the corpus callosum (CLOCCs). High-dose intravenous methylprednisolone improved their symptoms and imaging findings. CLOCCs should be considered in patients with neurological manifestation after COVID-19 vaccination.