A 58-year-old female patient presented to the hospital with the chief complaints of aphasia and cognitive decline that began 2 weeks prior to presentation (). Four weeks prior to the hospital visit, the patient had received the first dose of the COVID-19 vaccine (ChAdOx1 nCoV-19, Oxford Astra-Zeneca®). The patient did not experience any adverse events during the vaccination. In terms of medical history, she had been diagnosed with Graves’ disease 20 years prior and had received medical treatment at that time. Subsequently, the patient achieved complete remission and has not been taking any medications since then. Upon admission, the patient showed stable vital signs and was alert. Neurological examination revealed no limb weakness, sensory deficits, or cranial nerve deficits. Language assessment revealed transcortical aphasia and agraphia, with dyscalculia and finger agnosia. Blood test results were unremarkable, except for a decrease in hemoglobin level (Hb; 9.4 g/dL; normal range, 12–16 g/dL). Brain MRI revealed hyperintensity in the bilateral subcortical white matter and right periventricular area on both T2-weighted and fluid-attenuated inversion recovery images. Susceptibility-weighted imaging (SWI) revealed hypointensity in the same lesion area, and diffusion restriction was also observed on diffusion-weighted imaging, although without contrast enhancement (). Analysis of a cerebrospinal fluid (CSF) sample showed a white blood cell count of 4/mm3, protein of 43.6 mg/dL, and glucose level of 66 mg/dL (serum glucose, 154 mg/dL). The finding of a CSF to serum glucose ratio of 0.5 or less was not considered a significant finding, as it is likely attributed to a time delay in the lumbar puncture procedure. Considering the current test results, post-vaccination acute disseminated encephalomyelitis (ADEM) was suspected, and 1 g of methylprednisolone was administered intravenously daily for 5 days. Spinal cord MRI was performed to differentiate it from other demyelinating disorders of the CNS; however, the findings were unremarkable. The IgG index was 0.49, and CSF oligoclonal bands, serum anti-aquaporin 4 antibodies, and serum anti-myelin oligodendrocyte glycoprotein antibodies were negative. Following high-dose steroids therapy, the patient scored 21 on the Korean mini-mental state examination, showing a 3-point improvement in the “attention and calculation” domain compared to before steroid therapy. Aphasia also improved, and the patient was able to speak words and simple sentences. Moreover, the patient was able to perform one-digit addition and subtraction. However, cognitive decline persisted. Hence, intravenous immunoglobulin (IVIg) therapy was initiated at 400 mg/kg/day on day 13, lasting for 5 days. Agraphia and cognitive function improved slightly during IVIg therapy, but her platelet level dropped to 10.8 K on day 3 of IVIg administration (admission day 15), and a fever of ≥38°C persisted from day 5 of IVIg administration (admission day 17). Blood tests indicated pancytopenia (white blood cell count, 3,920/mm3; Hb, 6.8 g/dL; and platelet count, 44,000/mm3). The C-reactive protein level was 8.5 mg/dL (normal range 0.0–0.3 mg/dL), and procalcitonin was 0.54 ng/mL (normal range 0–0.5 ng/mL). Blood, sputum, and urine cultures were performed to identify the cause of fever, but findings were unremarkable. The serum viral antibody test results were negative. CSF samples were tested using polymerase chain reaction and were negative for herpes simplex virus, varicella-zoster virus, and Epstein–Barr virus. Chest and abdominal computed tomography did not indicate infection, but showed hepatomegaly and splenomegaly. Subsequently, the patient was referred to the hemato-oncology department for fever of unknown cause, and pancytopenia that lasted more than a week. HLH was suspected. Additional blood tests and bone marrow biopsies were also performed. Bone marrow biopsy did not indicate hemophagocytosis. However, six out of the eight HLH-2004 diagnostic criteria were met including fever, splenomegaly, cytopenia (Hb 6.8 g/dL and platelets 44,000/mm3), hypertriglyceridemia (triglycerides 268 mg/dL), increased ferritin (>1,675 mcg/L), and reduced natural killer cell (NK cell) activity (<40.0 pg./mL). As a results, the patient was diagnosed with probable HLH following COVID-19 vaccination, based on the temporal sequence, although it was not definitively proven. Splenectomy was planned to assess the preexisting causes of HLH (other than vaccination) and treatment. Unfortunately, the patient died on day 28 owing to sudden hypotension and multiple organ failure.