Vancomycin trough (Vt) concentrations of 15–20 mcg/mL have been associated with an increased rate of renal injury in adults. Current data in pediatrics suggests Vts of 15–20 mcg/mL do not increase the risk of renal injury in children admitted to a pediatric intensive care unit (PICU). The primary objective was to determine if a difference exists in the incidence of renal injury in PICU patients receiving a β-lactam as compared with vancomycin therapy with Vts of 15–20 mcg/mL. This was a retrospective cohort study conducted within a PICU within a freestanding tertiary care pediatric hospital. The records of children admitted to the PICU between 10/2008–6/2009 who received vancomycin for ≥48 h targeting higher Vt concentrations of ≥15 mcg/mL for pneumonia, bacteremia, and meningitis were reviewed. This cohort (V group) was compared to children admitted from July 2009–July 2013 who received cefepime or piperacillin/tazobactam for ≥72 h (B group). Serum creatinine values were collected from 48 h before until 48 h after discontinuation of therapy for calculation of estimated glomerular filtration rate. Renal injury was categorized according to pRIFLE. 57 and 112 patients were included in the V and B groups, respectively. The mean (SD) therapeutic dose of vancomycin was 63.5(17.3) mg/kg/day and the mean (SD) trough was 17.8(3.1). The mean (SD) dose of cefepime was 51(26) mg/kg/dose with an every 8 h interval. The mean (SD) dose of piperacillin/tazobactam was 77(22) mg/kg/dose with an every 6 h interval. The mean (SD) PRISM scores were 10.9(10.2), 4.24(6.4) for the V and B groups, respectively (p < 0.001). Five of 57 and 10 of 112 patients in the V and B groups, respectively, were classified as having injury according to pRIFLE. No patient was classified as having a degree of renal injury greater than the pRIFLE injury. The incidence of renal injury was 8.8% in the V group and 8.9% in the B group, respectively (p = 1). Our observations suggest that maintaining Vt concentrations ≥15 mcg/mL is not associated with an increased rate of renal injury as compared with β-lactam monotherapy in a PICU population.