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Background: Acute kidney injury (AKI) is a serious health problem in critically ill children. It is associated with poor treatment outcomes and high morbidity and mortality rates. Globally, one in three critically ill children suffers from acute kidney injury. However, limited data are available in Africa, particularly Ethiopia, which highlighting the risk factors related to acute kidney injury. Therefore, this study aimed to identify the risk factors associated with acute kidney injury among critically ill children admitted to the pediatric intensive care unit (PICU) at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia., Methods: A facility-based unmatched case-control study was carried out on 253 (85 cases and 168 controls) critically ill children admitted to the pediatric intensive care unit from January 2011 to December 2021. Participants were selected using a systematic random sampling technique for the control group and all cases consecutively. Data were collected using a structured checklist. Data were entered using Epi data version 4.6 and analyzed using SPSS version 25. Multivariable analysis was carried out using the adjusted odds ratio (aOR) with a 95% confidence interval (CI) to identify associated factors with acute kidney injury. Statistical significance was set at P < 0.05., Results: The median age of the participants was two years. Approximately 55.6% of cases and 53.1% of controls were females. The diagnosis of hypertension (aOR = 5.36; 95% CI: 2.06-13.93), shock (aOR = 3.88, 95% CI: 1.85-8.12), exposure to nephrotoxic drugs (aOR = 4.09; 95% CI: 1. 45- 11.59), sepsis or infection aOR = 3.36; 95% CI: 1.42-7.99), nephritic syndrome (aOR = 2.97; 95% CI:1.19, 7.43), and use of mechanical ventilation aOR = 2.25, 95% CI: 1.12, 4.51) were significantly associated factors with acute kidney injury., Conclusion: The diagnosis of sepsis or infection, hypertension, shock, nephrotoxic drugs, demand for mechanical ventilation support, and nephritic syndrome increased the risk of AKI among critically ill children. Multiple risk factors for AKI are associated with illness and severity. All measures that ensure adequate renal perfusion must be taken in critically ill children with identified risk factors to prevent the development of AKI., (© 2023. BioMed Central Ltd., part of Springer Nature.)