background: Infection prevention and control professionals must continually work to develop best practices to prevent transmission of epidemiologically important microorganisms in acute care hospitals. While most healthcare facilities use transmission-based precautions to prevent transmission, monitoring of compliance of these precautions is not universal. methods: A retrospective longitudinal study was performed using secondary data collected at an acute care hospital in southern California. Correlation tests examined association between compliance and the independent variables. Multiple regression tests determined predictors of compliance. results: Six variables were significantly associated with mean compliance. Ten variables significantly predicted compliance: documented daily chlorhexidine gluconate (CHG) bath, precaution sign on door, accurate isolation in electronic medical record, disposable/dedicated equipment used, staff verbalize contact time for disinfectant, hand hygiene on room entry, staff remove gown/gloves before exiting room, staff wear mask in droplet isolation room, patient’s door kept closed, and hand hygiene with soap and water on room exit from C. difficile rooms. conclusion: Sustainable systems should be designed to perform surveillance to ensure continual employee compliance with transmission-based precautions. The intent of such programs is to ultimately decrease the transmission of multi-drug resistant microorganisms in acute care hospitals and the community.