Abstract Aim of the study: We aimed to investigate the characteristics of acute-on-chronic liver failure (ACLF) and factors associated with 28-day mortality in patients with ACLF. Material and methods: This prospective study included ACLF patients based on the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium criteria, admitted between March 2021 and February 2022. We examined variables associated with 28-day mortality using multivariate Cox regression analysis. Results: Of 326 patients admitted with acute decompensation (AD) of cirrhosis, 109 (33.44%) patients were diagnosed with ACLF (mean age 63.61 ±11.15 years, 65.14% males). Of these, 26.61%, 35.78%, and 37.61% of patients were in ACLF grades 1, 2, and 3 respectively. HCV (80.73%) was the main aetiology of cirrhosis. Upper gastrointestinal bleeding (25.69%) was the most common trigger. Kidney failure (73.39%) was the most common organ failure. The 28-day mortality rate was 66.97%. Cox regression analysis revealed that the existence of 2 (HR = 6.99, 95% CI: 2.68-18.25, p < 0.0001) or ≥ 3 (HR = 9.34, 95% CI: 3.6-24.74, p < 0.0001) organ failures, hepatic encephalopathy (HR = 2.96, 95% CI: 1.27-6.94, p = 0.01), and elevated serum bilirubin (HR = 1.03, 95% CI: 1.00-1.06, p = 0.04) were independent predictors for 28-day mortality, while shifting blood pH to the normal range was associated with a decrease in the HR of ACLF mortality (HR = 0.03, 95% CI: 0.002-0.44, p = 0.01). Conclusions: ACLF has a very high 28-day mortality, which is associated with the existence of 2 or more organ failures, hepatic encephalopathy, elevated serum bilirubin, and low blood pH.