Objective:Central-line–associated bloodstream infections (CLABSI) cause morbidity and mortality in critically ill children. We examined novel and/or modifiable risk factors for CLABSI to identify new potential targets for infection prevention strategies.Methods:This single-center retrospective matched case-control study of pediatric intensive care unit (PICU) patients was conducted in a 60-bed PICU from April 1, 2013, to December 31, 2017. Case patients were in the PICU, had a central venous catheter (CVC), and developed a CLABSI. Control patients were in the PICU for ≥2 days, had a CVC for ≥3 days, and did not develop a CLABSI. Cases and controls were matched 1:4 on age, number of complex chronic conditions, and hospital length of stay.Results:Overall, 72 CLABSIs were matched to 281 controls. Univariate analysis revealed 14 risk factors, and 4 remained significant in multivariable analysis: total number of central line accesses in the 3 days preceding CLABSI (80+ accesses: OR, 4.8; P = .01), acute behavioral health needs (OR, 3.2; P = .02), CVC duration >7 days (8–14 days: OR, 4.2; P = .01; 15–29 days: OR, 9.8; P < .01; 30–59 days: OR, 17.3; P < .01; 60–89 days: OR, 39.8; P < .01; 90+ days: OR, 4.9; P = .01), and hematologic/immunologic disease (OR, 1.5; P = .05).Conclusions:Novel risk factors for CLABSI in PICU patients include acute behavioral health needs and >80 CVC accesses in the 3 days before CLABSI. Interventions focused on these factors may reduce CLABSIs in this high-risk population.