Background: With multiple comorbidities and frequent exposures to antibiotics, patients in skilled nursing facilities (SNFs) are much more vulnerable to healthcare-acquired infections. We conducted a quality-improvement, retrospective analysis of all patients with Objectives: To assess the value of providing probiotic therapy to SNF patients at risk for CDI. Patients and methods: Patients receiving oral or enteral feeding with antibiotics ordered were eligible to receive probiotics. The incremental cost of CDI prevention, treatment and related care were calculated and compared for each phase of probiotic policy change and feeding type. ASP records for the oral probiotic and level of treatment were used in modelling the cost-effectiveness. Results: From quality improvement initiatives aimed at preventing facility-onset (FO) CDI, to ASP policies, probiotic formulations and delegation of ordering authority, the days of acute care treatment required was significantly reduced over the different phases of implementation [152 to 48, OR = 0.22 (0.16-0.31) to 4, OR = 0.08 (0.03-0.23)] after reducing total CDI from 5.8 to 0.3 cases per 10 000 patient-days. The annual cost of oral probiotics increased from $6019 to $14 652 but the modelled net annual savings for the facility was $72 544-$154 085. Conclusions: With optimization, the use of probiotics for CDI prevention at an SNF was safe, efficacious and cost-effective.