Background: Vertical interventions in public health are disease focused, whereas horizontal interventions are systems based. The new concept of “diagonal interventions” merging these 2 approaches is also applicable to infection prevention (IP). During fiscal year (FY) 2016, our facility identified 14 central-line–associated blood stream infections (CLABSIs), resulting in a rate of 1.44 cases per 1,000 catheter days, twice that of FY2015 (0.75 cases per 1,000 catheter days). Methods: Focusing on a horizontal “systems building” approach, the IP team used previously developed informal relationships to mobilize a formal multidisciplinary team comprised of IP, nursing educators, the intravenous therapy team, and frontline staff. Initially charged with implementation of disinfecting caps for needleless connectors, the IP team capitalized on this multidisciplinary resource to launch a multifaceted communication and education campaign supporting CLABSI-specific interventions. For vertical interventions, an IP risk assessment revealed variations in care and maintenance of central lines and the need for staff education. A literature search was conducted to identify evidence-based strategies for reducing CLABSIs, leading to the development of a nursing-led bundle of the following elements: (1) education on CDC hand hygiene guidelines, (2) central-line competency validation and assessment for nurses on hire and annually, (3) standardized processes across all wards for central-line dressing changes (“timed on Tuesdays”), and (4) a pilot program for disinfecting caps on 3 inpatient wards. The IP team identified CLABSIs using standard NHSN definitions. Catheter days were obtained on each inpatient ward. Unit-specific rates were calculated per 1,000 catheter days. Mann-Kendall Test was used to assess rate trends over time, whereas the Fisher exact test was used for rate comparisons. A P < .05 was considered significant. Results: CLABSI rates decreased from 1.44 in FY2016 to 0.12 in FY2019 (Kendall τ = −0.5; P < .001) (Fig. 1). During the 3-month pilot phase of disinfecting caps, no CLABSIs were identified on 3 intervention wards versus 3 CLABSIs on control wards (rate, 0 vs 2.57; P = .27) and 1 CLABSI in the 3-month baseline period prior to the intervention (0 vs 0.40; P > .99). Disinfecting caps were expanded house-wide beginning in FY2018. The multidisciplinary team evolved into a sustained collaborative (“Scrub Club”) meeting biweekly. They have now broadened their focus to quality improvement initiatives for multiple healthcare-associated infections (HAIs). Conclusions: The IP team has traditionally utilized vertical models of intervention. The use of “diagonal” models that incorporate horizontal health systems strengthening can transform multidisciplinary partnerships into long-term collaboratives essential for sustained reduction of HAIs.