Marked elevation in aminotransferases (≥1000 IU/l) is typically associated with acute liver injury. Here, we hypothesized that the cause of elevation in aminotransferases ≥1000 in patients with cirrhosis is likely due to a limited number of disorders and may be associated with poor outcomes. We aimed to investigate the most common etiologies of acute elevations in aminotransferases in patients with cirrhosis, and to examine their associated outcomes. From May 2012 to December 2022, all hospitalized patients with cirrhosis and an aspartate aminotransferase or alanine aminotransferase ≥ 1000 IU/l were identified through Medical University of South Carolina's Clinical Data Warehouse. Complete clinical data were abstracted for each patient, and in-hospital mortality was examined. The cohort was made up of 152 patients, who were 57 ± 12 years old, with 51 (34%) women. Underlying liver disease included mainly hepatitis C cirrhosis, alcohol-related cirrhosis, metabolic dysfunction-associated steatohepatitis cirrhosis, autoimmune cirrhosis, primary sclerosing cholangitis cirrhosis, and cryptogenic cirrhosis. The most common cause of marked elevation in aminotransferases in cirrhotic patients was ischemic hepatitis (71%), followed by chemoembolization (7%), autoimmune hepatitis (6%), drug-induced liver injury (3%), post-transjugular intrahepatic portosystemic shunt placement (3%), rhabdomyolysis (3%), and hepatitis C (2%). During hospitalization and over a 1-month follow-up period, the mortality rate in patients with ischemic hepatitis was 73% (79/108), while that for other causes of liver injury was 20% (9/44). Ischemic hepatitis is the leading cause of marked elevation of aminotransferases in patients with cirrhosis, with distinctive clinical characteristics than other etiologies, and significantly poorer outcomes.