Abstract Background Contrast-induced encephalopathy (CIE) is a well-known complication of iodinated contrast agents during angiography and vascular interventions. It can manifest as hemiparesis, cortical blindness, speech changes, Parkinsonism, confusion, seizure, and coma. Most of the reported CIE cases have been transient and reversible. Irreversible fatal CIE cases have been rarely reported. All the fatal CIE cases reported involved the use of ionic high osmolar contrast agents. Here, we document a heretofore unreported fatal CIE after digital subtraction angiography (DSA) using iopamidol, which is a type of non-ionic monomer low osmolar contrast agent. Case presentation A 71-year-old woman was admitted to our Department of Neurology for tinnitus in the head. The cerebral magnetic resonance angiography (MRA) detected atherosclerotic cerebral arteries and bilateral stenosis of the middle cerebral arteries. The patient underwent DSA for further diagnostic work-up. The total amount of iopamidol used during the procedure was 110 ml. The patient experienced headache during the procedure, followed by dizziness with nausea and vomiting. Despite treatment with anti-oedema medications, her clinical status was gradually deteriorating and ended up with deep coma due to irreversible cerebral oedema which was confirmed by cerebral computed tomography (CT). Finally, the patient died 56 days after the procedure due to irreversible fatal cerebral oedema. Conclusions This report documents that iopamidol-induced encephalopathy may not always have a benign outcome and can result in irreversible fatal cerebral oedema.