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Background: Critically ill children are vulnerable to acute kidney injury (AKI) and are often exposed to nephrotoxic medications. Objectives: We aimed to investigate the association between nephrotoxic medications and the risk of AKI in critically ill children admitted to our paediatric intensive care unit (PICU). Methods: Patients aged > 1 month to ≤18 years old were prospectively recruited from 6/2020 to 6/2021. The medication records from 14 days prior to PICU admission to PICU discharge were reviewed. Medication-exposure intensity was defined as the number of concomitant nephrotoxic medications. The relative risk (RR) of nephrotoxic medication exposure indices and other potential predictors for AKI development were determined. Results: Altogether 253 episodes of admissions (median [IQR] age of 4.9 [9.6] years) were enrolled. The AKI incidence was 41.9% and 69.2% of the patients were exposed to ≥1 of the 47 nephrotoxic medications. The total nephrotoxic medication dose (RR: 1.01 [1.00, 1.02]) and medication-exposure intensity (RR: 1.381 [1.101, 1.732]) were significantly associated with AKI development. The risk of AKI increased when the medication-exposure intensity was ≥4 (RR: 3.687 (1.320, 10.301)). During their PICU stay, children with AKI received a higher number (P <.01), total dose (P <.01) and medication exposure intensity (P <.01) of nephrotoxic medications. Children with AKI who received nephrotoxic medications were more likely to have a persistently higher peak-to-baseline ratio (P =.046). Conclusion: Nephrotoxic medication exposure significantly increased the risk of AKI development among critically ill children. The use of nephrotoxic medications among critically ill children at risk for AKI should be monitored frequently. [ABSTRACT FROM AUTHOR]