PURPOSE To study selective use of antibiotic-impregnated catheters in children at increased risk of venous catheter-related infections (CRIs). MATERIALS AND METHODS From December 2008 to June 2009, 428 peripherally inserted central catheters (PICCs) were placed by the interventional radiology service of a large metropolitan children's hospital. This retrospective study analyzed demographic and outcome data for the 125 patients in this group at high risk for venous CRI. Patients at high risk were those with active systemic infection, previous complicated central venous access, intensive care unit (ICU) admission, intestinal failure, transplantation, complex congenital heart disease, or renal failure. Patients (age, 7.6 y ± 7.0; 73 male and 52 female) received a conventional or antibiotic-impregnated PICC, with 17 receiving more than one catheter. RESULTS Of the 146 of 428 qualifying patient encounters (34%), 53 patients received an antibiotic-impregnated PICC and 93 received a conventional PICC, representing 5,080 total catheter-days (CDs). The rates of CRIs per 1,000 CDs, including catheter exit site infections and catheter-related bloodstream infections, were 0.86 for antibiotic-impregnated PICCs and 5.5 for conventional PICCs (P = .036). A propensity-based model predicts 15-fold greater infection-free survival over the lifetime of the catheter in patients who receive an antibiotic-impregnated PICC (P < .001). Antibiotic-impregnated PICC recipients with active infection or ICU admission at the time of insertion had no catheter-associated infections, compared with 3.42 and 9.46 infections per 1,000 CDs, respectively, for patients who received conventional PICCs. Patients with intestinal failure had 1.49 and 10 infections per 1,000 CDs with antibiotic-impregnated versus conventional PICCs, respectively. CONCLUSIONS Antibiotic-impregnated long-term PICCs significantly improve infection-free catheter survival in pediatric patients at high risk.