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Infections worsen survival in cirrhosis; however, simple predictors of survival in infection‐related acute‐on‐chronic liver failure (I‐ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End‐stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥7) and 30‐day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30‐day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I‐ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non‐SBP infections. Independent predictors of poor 30‐day survival were I‐ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin. Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I‐ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival. (Hepatology 2014;60:250–256)