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Background & Aims: Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis., Methods: This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points., Results: There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59-1.77; p = 0.94) and 1.28 (95% CI 0.75-2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated., Conclusions: Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis., Lay Summary: Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. CLINICALTRIALS., Gov Identifier: NCT03205345., Competing Interests: Conflict of interest James Robinson, Jean L. Chan and David Hagerty were employees of Conatus Pharmaceuticals, Inc., during the conduct of the study. Nicole Wedick was a consultant employed by Conatus Pharmaceuticals, Inc., and reports personal fees from SimulStat, Inc., during the conduct of the study. Catherine Frenette reports research funding from Conatus Pharmaceuticals, Inc., during the conduct of this study and personal fees from Conatus Pharmaceuticals, Inc., outside of the submitted work. Kris Kowdley reports grants from Conatus Pharmaceuticals, Inc., during the conduct of the study; personal fees from Abbvie, Gilead and Intercept, outside of the submitted work; grants from Enanta, Genfit, Gilead, CymaBay, HighTide, Intercept, Allergan and LaJolla, outside of the submitted work; royalties from UpToDate, outside of the submitted work. Kris Kowdley was on the Advisory Board of Assembly Biosciences, Blade, Enanta, Genefit, Gillead, CymaBay and Merck and was a consultant for HighTide and Intercept, outside of the submitted work. Guy Neff reports grants from Echosens and personal fees from Intercept, outside the submitted work. Parvez Mantry reports personal fees from Gilead, Intercept, Salix, Eisai, Abbvie and grants from Allergan, Genfit, Bristol-Myers, Galmed, Viking, Pfizer, Merck, outside the submitted work. Ethan Weinberg reports personal fees from Mallinckrodt Pharmaceuticals and from Sequana, outside the submitted work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)