The transmission of Clostridium difficile infection (CDI) is evident in healthcare facilities across the country and poses a risk for patients and communities. A comprehensive infection control program along with an active surveillance process was developed and implemented in a 50-bed long-term acute care hospital (LTACH) in the southeastern United States. Patients are admitted from surrounding hospitals, have an expected stay of at least 25 days, and are acutely ill. The majority of the patient population is ventilator dependent, immunocompromised, and treated with antimicrobials. The program, implemented in December 2009, utilized a tiered approach that included environmental cleaning and disinfection, diagnostics and surveillance, and infection control measures including antibiotic stewardship. The goal of this study was to decrease the incidence rate of CDI 15% by June 2010. Based upon year-end results, the facility achieved a 27.61% decrease in the CDI rate. During the following 12 months, the program continued to demonstrate sustainability resulting in a 23.0% decrease in the CDI rate. This program was successful in decreasing the incidence of CDI in the LTACH creating a safe and cost-effective environment for patients, families, and the community.