OBJECTIVES: Hyperglycemia is common and may be a risk factor for nosocomial infections, including central catheter-associated bloodstream infections in critically ill children. It is unknown whether hyperglycemia at the time of acquiring central catheter-associated bloodstream infections in pediatric critical illness is associated with worse outcomes. We hypothesized that hyperglycemia (blood glucose concentration > 126 mg/dL [> 7 mmol/L]) at the time of acquiring central catheter-associated bloodstream infections (from 4 d prior to the day of first positive blood culture, i.e., central catheter-associated bloodstream infections) in critically ill children is common and associated with ICU mortality. DESIGN: Retrospective observational cohort study. SETTING: Fifty-five-bed PICU and 26-bed cardiac ICU at an academic freestanding children's hospital. PATIENTS: One hundred sixteen consecutively admitted critically ill children from January 1, 2008, to June 30, 2012, who were 0-21 years with central catheter-associated bloodstream infections were included. We excluded children with diabetes mellitus, metabolic disorders, and those with a "do not attempt resuscitation" order. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study cohort had an overall ICU mortality of 23%, with 48% of subjects developing hyperglycemia at the time of acquiring central catheter-associated bloodstream infections. Compared with survivors, nonsurvivors experienced more hyperglycemia both at the time of acquiring central catheter-associated bloodstream infections and subsequently. Median blood glucose at the time of acquiring central catheter-associated bloodstream infections was higher in nonsurvivors compared with survivors (139.5 mg/dL [7.7 mmol/L] vs 111 mg/dL [6.2 mmol/L]; p < 0.001) with 70% of nonsurvivors experiencing blood glucose greater than 126 mg/dL (> 7 mmol/L) during the 7 days following central catheter-associated bloodstream infections (in comparison to 45% of survivors; p = 0.03). After controlling for severity of illness and interventions, hyperglycemia at the time of acquiring central catheter-associated bloodstream infections was independently associated with ICU mortality (adjusted odds ratio, 1.9; 95% CI, 1.1-6.4; p = 0.03), in addition to other risk factors for ICU mortality (vasopressor use and severity of organ dysfunction). CONCLUSIONS: Hyperglycemia at the time of acquiring central catheter-associated bloodstream infections is common and associated with ICU mortality in critically ill children. Strategies to monitor and control blood glucose to avoid hyperglycemia may improve outcomes in critically ill children experiencing central catheter-associated bloodstream infections.