Background: Central-line–associated bloodstream infection (CLABSI) rates have steadily decreased as evidence-based prevention bundles were implemented. Bone marrow transplant (BMT) patients are at increased risk for CLABSI due to immunosuppression, prolonged central-line utilization, and frequent central-line accesses. We assessed the impact of an enhanced prevention bundle on BMT nonmucosal barrier injury CLABSI rates. Methods: The University of Iowa Hospitals & Clinics is an 811-bed academic medical center that houses the only BMT program in Iowa. During October 2018, we added 3 interventions to the ongoing CLABSI prevention bundle in our BMT inpatient unit: (1) a standardized 2-person dressing change team, (2) enhanced quality daily chlorhexidine treatments, and (3) staff and patient line-care stewardship. The bundle included training of nurse champions to execute a team approach to changing central-line dressings. Standard process description and supplies are contained in a cart. In addition, 2 sets of sterile hands and a second person to monitor for breaches in sterile procedure are available. Site disinfection with chlorhexidine scrub and dry time are monitored. Training on quality chlorhexidine bathing includes evaluation of preferred product, application per product instructions for use and protection of the central-line site with a waterproof shoulder length glove. In addition to routine BMT education, staff and patients are instructed on device stewardship during dressing changes. CLABSIs are monitored using NHSN definitions. We performed an interrupted time-series analysis to determine the impact of our enhanced prevention bundle on CLABSI rates in the BMT unit. We used monthly CLABSI rates since January 2017 until the intervention (October 2018) as baseline. Because the BMT changed locations in December 2018, we included both time points in our analysis. For a sensitivity analysis, we assessed the impact of the enhanced prevention bundle in a hematology-oncology unit (March 2019) that did not change locations. Results: During the period preceding bundle implementation, the CLABSI rate was 2.2 per 1,000 central-line days. After the intervention, the rate decreased to 0.6 CLABSI per 1,000 central-line days (P = .03). The move in unit location did not have a significant impact on CLABSI rates (P = .85). CLABSI rates also decreased from 1.6 per 1,000 central-line days to 0 per 1,000 central-line days (P < .01) in the hematology-oncology unit. Conclusions: An enhanced CLABSI prevention bundle was associated with significant decreases in CLABSI rates in 2 high-risk units. Novel infection prevention bundle elements should be considered for special populations when all other evidence-based recommendations have been implemented.