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Compare the rates of acute kidney injury in critically ill children treated with vancomycin and piperacillin-tazobactam versus vancomycin and ceftriaxone.Retrospective cohort study.A large tertiary care children’s hospital in an urban setting.Children greater than or equal to 2 months old admitted to the PICU who received greater than or equal to 48 consecutive hours of vancomycin and piperacillin-tazobactam or vancomycin and ceftriaxone.None.Acute kidney injury was defined as a minimum 50% increase in serum creatinine, adjusted for total fluid balance, from baseline over a 48-hour period. Bivariate analysis compared treatment groups and acute kidney injury groups. A multivariable logistic regression model was fit for acute kidney injury including covariable analysis. The study included 93 children. There were no differences between treatment groups in terms of age, severity of illness, baseline renal function, vancomycin dosing, or vancomycin trough concentrations. Children who received vancomycin and piperacillin-tazobactam had a higher cumulative frequency of acute kidney injury than those who received vancomycin and ceftriaxone 915/58 [25.9%] vs 3/35 [8.6%]; p = 0.041). After controlling for vancomycin trough concentration, age, concurrent nephrotoxin exposure, and use of vasopressors, exposure to piperacillin-tazobactam significantly increased the risk of acute kidney injury (adjusted odds ratio, 4.55; 95% CI [1.11–18.7]; p = 0.035) compared with ceftriaxone. Use of vasopressors (adjusted odds ratio, 3.73 [95% CI, 1.14–12.3]) and a vancomycin trough greater than or equal to 15 mg/dL (adjusted odds ratio, 4.12 [95% CI, 1.12–15.2)] was also associated with acute kidney injury. Length of stay was longer in children with acute kidney injury (median, 18.0 days; interquartile range, 7.76–29.7) compared with those without acute kidney injury (median, 6.21 days; interquartile range, 2.92–15.6; p = 0.017).In critically ill children, acute kidney injury occurred more in patients treated with vancomycin and piperacillin-tazobactam versus vancomycin plus ceftriaxone. After controlling for covariates, exposure to piperacillin-tazobactam was associated with an increased odds of acute kidney injury development.