A 65-year-old female patient visited the emergency department with a confusional mentality. The symptoms of the patient were initially suspected to be due to an overdose of her usual antipsychotics, and we planned to instantly discontinue her medications. However, her hemoglobin was observed to be 5.5 g/dL. Although the transfusion-related antibody screening test was positive, the patient received 1 point for packed red blood cells because of severe anemia. The same antibody screening test performed 10 years previously yielded negative results. She returned to the emergency department a day later with recurrent seizures. Brain magnetic resonance imaging (MRI) showed multiple patches of high signal intensity in the fluid-attenuated inversion recovery image and multiple leptomeningeal enhancements on contrast-enhanced T1-weighted imaging (Fig. 1). Cerebrospinal fluid analysis showed no pleocytosis, but the consciousness of the patient deteriorated to semicoma within 3 days. Follow-up brain MRI showed multiple diffusion-restrictive lesions with diffuse punctuated hemorrhages and extensive mass effect (Fig. 2). Posterior reversible encephalopathy syndrome (PRES) was considered as a differential diagnosis, but concomitant massive edema, diffusion-restrictive lesions, and extensive hemorrhage were more consistent with acute hemorrhagic leukoencephalitis (AHLE) than PRES. In addition, recent medications were observed to be unrelated, and laboratory tests, including autoimmune diseases, infectious diseases, metabolic diseases, and thrombosis abnormalities, including coronavirus disease 2019, were all negative. Despite extensive, intensive care with 5 days of steroid pulse therapy, the patient progressed to a coma and died of multiorgan failure. AHLE is a severe form of acute demyelinating encephalomyelitis [1,2]. Herein, we report a case of MRI-suspected AHLE that was associated with an immunologic response to blood transfusion in a patient with a positive antibody screening test.