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Objective:A guideline for the prevention of Clostridioides difficile infection (CDI) in 127 Veterans Health Administration acute-care facilities was implemented in July 2012. Beginning in 2015, a targeted assessment for prevention strategy was used to evaluate facilities for hospital-onset healthcare-facility–associated CDIs to focus prevention efforts where they might have the most impact in reaching a reduction goal of 30% nationwide.Methods:We calculated standardized infection ratios (SIRs) and cumulative attributable differences (CADs) using a national data baseline. Facilities were ranked by CAD, and those with the 10 highest CAD values were targeted for periodic conference calls or a site visit from January 2016–September 2019.Results:The hospital-onset healthcare-facility–associated CDI rate in the 10 facilities with the highest CADs declined 56% during the process improvement period, compared to a 44% decline in the 117 nonintervention facilities (P = .03).Conclusion:Process improvement interventions targeting facilities ranked by CAD values may be an efficient strategy for decreasing CDI rates in a large healthcare system.