Purpose: A 43-year-old female with a history of Roux-en-Y Gastric Bypass performed 10 years ago presented with abdominal pain and lower extremity edema. A CT scan showed a distended remnant gastric pouch. Upper endoscopy was performed showing a normal esophagus without esophageal varices and ulceration at the gastro-jejunal anastomosis. The remnant stomach and a small portion of the duodenum were excised for a suspected gastro-gastric fistula. Pathology showed chronic gastritis, chronic duodenitis and gastric mucosal ulceration with reparative changes and no Helicobacter pylori infection. The patient was discharged and was subsequently admitted for purulent drainage from her surgical wound. Cultures grew enterobacter and she was started on the appropriate antibiotics with confirmed laboratory sensitivity. Her mental status suddenly became increasingly altered and she became combative. On physical exam, she had icteric sclera and jaundice with no manifestations of chronic liver disease. She had a direct hyperbilirubinemia with an ammonia level of 191 UMOL/L. Laboratory evaluation did not reveal any deficiencies in thiamine, vitamin B12, folate, copper, or zinc. Vitamin D was low with a value of 17.8 NG/mL. Imaging studies revealed hepatic steatosis with no evidence of biliary obstruction. She was started on lactulose and rifaximin through a naso-gastric tube and also given lactulose enemas. She was also started on daily intravenous thiamine. Imaging of the head and lumbar puncture were normal. She had a rapid deterioration and required intubation shortly thereafter. Despite treatment with lactulose and rifaximin, her ammonia continued to remain extremely high. She required high doses of vasopressors and developed global anoxic brain injury. The family decided to take comfort care measures at that time. The differential diagnosis for non-hepatic hyperammonemia includes medications, hyperalimentation, infections with urease producing bacteria (ex. Helicobacter pylori), surgery induced nutritional deficiencies and errors of metabolism. All potentials in the differential had been excluded for this patient except errors of metabolism. An exceedingly rare phenomenon with a nearly identical presentation has been previously described involving female patients developing fatal hyperammonemic encephalopathy after gastric bypass surgery, some as much as 28 years after their surgery. The mechanism remains unknown, but is thought to involve the unmasking of inborn errors of urea metabolism, the most common of which is ornithine transcarbamylase deficiency. Clinicians and bariatric centers must become more aware of this new phenomenon as more studies are needed to reveal its natural history and underlying cause.