OBJECTIVE To evaluate the impact of no-touch terminal room no-touch disinfection using ultraviolet wavelength C germicidal irradiation (UVGI) on C. difficile infection (CDI) rates on inpatient units with persistently high rates of CDI despite infection control measures. DESIGN Interrupted time-series analysis with a comparison arm. SETTING 3 adult hematology-oncology units in a large, tertiary-care hospital. METHODS We conducted a 12-month prospective valuation of UVGI. Rooms of patients with CDI or on contact precautions were targeted for UVGI upon discharge using an electronic patient flow system. Incidence rates of healthcare-onset CDI were compared for the baseline period (January 2013-December 2013) and intervention period (February 2014-January 2015) on study units and non-study units using a mixed-effects Poisson regression model with random effects for unit and time in months. RESULTS During a 52-week intervention period, UVGI was deployed for 542 of 2,569 of all patient discharges (21.1%) on the 3 study units. The CDI rate declined 25% on study units and increased 16% on non-study units during the intervention compared to the baseline period. We detected a significant association between UVGI and decrease in CDI incidence (incidence rate ratio [IRR], 0.49; 95% confidence interval [CI], 0.26-0.94; P=.03) on the study units but not on the non-study units. The impact of UVGI use on average room-cleaning time and turnaround time was negligible compared to the baseline period. CONCLUSIONS Targeted deployment of UVGI to rooms of high-risk patients at discharge resulted in a substantial reduction of CDI incidence without adversely impacting room turnaround. Infect Control Hosp Epidemiol 2016;1-6.