OBJECTIVES: Hyperamylasemia (HA) is often reported in patients with acute liver failure (ALF). Direct toxic effects of acetaminophen on the pancreas have been postulated, but the occurrence of HA in other etiologies raises the question of whether multiorgan failure is part of the pathogenesis of HA in this setting. Our main aim was to describe and analyze the incidence, clinical characteristics, and outcomes of HA in ALF of different etiologies. METHODS: Patients enrolled in the Acute Liver Failure Study Group registry with an admission amylase value available were included. For the purpose of this analysis, HA was defined as ≥3x upper limits of normal. Patients were classified as having acetaminophen (APAP)- or non-APAP-induced ALF, and by amylase group: normal (<115), mildly elevated (115-345), or HA (>345). Significant variables identified by univariate analysis were added to a multiple linear regression model. The primary outcome was overall survival. RESULTS: In total, 622 eligible patients were identified in the database, including 287 (46%) with APAP-induced ALF; 76 (12%) patients met the criteria for HA. Among patients with HA, 7 (9%) had documented clinical pancreatitis. The incidence of HA was similar among APAP (13%) and non-APAP (12%) patients. Although HA was associated with renal failure and greater Model for End-stage Liver Disease scores for both groups, HA was not an independent predictor of mortality in multivariate analysis. CONCLUSIONS: Although not an independent predictor of mortality, HA in ALF was present in all etiologies and was associated with diminished overall survival. HA appeared to be related to renal dysfunction in both groups and multiorgan failure in non-APAP ALF. © 2009 by the American College of Gastroenterology.