Hyperammonemic encephalopathy (HAE) from extrahepatic causes is increasingly being recognized. Refeeding syndrome is characterized by severe fluid and electrolyte shifts following the reintroduction of nutrition. We describe the case of a 67-year-old man with bilateral maxillary sinus squamous cell carcinoma on nivolumab who became comatose after initiation of enteral feeding. Initial workup was notable for severe hypophosphatemia (<1 mg/dL) and markedly elevated ammonia (226 µmol/L). Neuroimaging was unrevealing. Correction of hypophosphatemia did not improve mental status. Ammonia levels briefly decreased while holding enteral feeding but worsened again on resumption. High-volume continuous renal replacement therapy was recommended but deferred in accordance with family wishes. We hypothesize that HAE may have been precipitated by a combination of refeeding-induced high nitrogen burden and limited detoxification via the urea cycle and extrahepatic pathways in the setting of severe protein-energy malnutrition and underlying malignancy. Nivolumab could have contributed as well.