To determine the etiology and outcomes of critically ill patients with severe hyperammonemia.Retrospective observational study of adults (18 years or older) admitted to a MICU from 2007 to 2016 who had a serum ammonia level >180 μmol/L (3 times the upper limit of normal).The 78 patients (45 male, 32 female) had a median age of 52 (interquartile range [IQR] 46-58) years. Hyperammonemia occurred most often with acute-on-chronic liver failure (ACLF) (49 %) or decompensated cirrhosis (27 %) and less often as a consequence of prior gastric bypass (9%), acute hepatic failure (6%), or valproic acid (3%). Median serum ammonia level was 201 μmol/L (IQR 126-265, range 18-736) on admission, with peak value of 245 μmol/L (IQR 205-336, range 185-842). Fifty (64%) patients died during the hospitalization. Cerebral edema was documented in 8 (10%) patients, only one of whom survived. Six of the 8 patients with cerebral edema had hyperammonemia related to ACLF, giving an incidence of 14% in this subset of patients. Neither mortality nor cerebral edema was associated with peak ammonia level.Critically ill patients with severe hyperammonemia have a high mortality rate and are at risk of developing cerebral edema.