ABSTRACT Background: Acute respiratory distress syndrome (ARDS) is an acute condition marked by bilateral lung infiltrates and hypoxemia within one week of an inciting event. Despite advances in critical care, ARDS continues to be associated with high mortality and prolonged hospital stays. Mortality is influenced by patient characteristics, disease severity, treatment strategies, and complications. However, data on ARDS outcomes in Ethiopia, particularly in the Amhara region, remain limited. Objectives:This study aimed to determine in-hospital mortality of ARDS and associated factors in intensive care units of TibebeGhion and FelegeHiwot Specialized Hospitals, Bahir Dar, Ethiopia, from November 2020 to November 2025. Methods: A retrospective cohort study was conducted using 374 medical records of adult ARDS patients. Data were collected from December 15, 2025, to January 10, 2026, using a structured data extraction tool. Data were entered into Kobo Toolbox and analyzed using SPSS version 27. Bivariate and multivariable logistic regression analyses were performed to identify factors associated with in-hospital mortality. Results:The study demonstrated that in-hospital mortality of ARDS was 63.1%(95% CI: 58.2%–68.0%). Multivariable logistic regression analysis identified;low GCS (8–12: AOR = 2.23, 95% CI 1.16–4.30; <8: AOR = 2.83, 95% CI 1.03–7.80), moderate (AOR = 2.20, 95% CI 1.14–4.26) and severe ARDS (AOR = 3.02, 95% CI 1.49–6.10), extra-pulmonary sepsis (AOR = 2.98, 95% CI 1.13–7.91), liberal fluid management (AOR = 3.27, 95% CI 1.55–6.91), and complications such as VAP(AOR = 2.95, 95% CI 1.02–8.54) and sepsis (AOR = 4.28, 95% CI 2.04–8.98) as independent predictors of in-hospital mortality. Conclusion: The study demonstrated that in-hospital mortality was higher than rates reported in developed countries and in most developing nations. Various factors were identified as independent predictors of in-hospital mortality. These findings emphasize the urgent need for targeted interventions to enhance the quality of critical care for patients with ARDS.