Over the past decade, efforts led by the U.S. Department of Health and Human Services (HHS) have reduced healthcare-associated infections in acute care settings nationally. In 2013, HHS identified that the next phase of these healthcare-associated infection reduction initiatives would target long-term care facilities through the publication of a new chapter in the National Action Plan to Prevent Health Care Associated Infections devoted to this setting. Long-term care facilities are nursing facilities that provide “medical, skilled nursing and rehabilitative services on an inpatient basis to individuals who need assistance preforming activities of daily living, such as bathing and dressing”. These facilities are the primary residence for 2.5 million, predominantly elderly Americans and represented $143 billion nationally in healthcare costs as of 2010. Accordingly, it is a national priority to reduce healthcare-associated infections in this setting and protect this vulnerable population. Healthcare-associated infections caused by multidrug-resistant organisms (MDROs) are a particular burden in the long-term care population. These pathogens, usually bacteria, are defined as being resistant to one or more classes of antimicrobial agents. However, MDROs frequently exhibit resistance to nearly all antimicrobial drugs. Clinical infection control guidelines recommend isolation precautions to prevent MDRO transmission, based on evidence collected in acute care settings. However, the limited evidence that is available from studies in long-term care facilities suggests that isolation precautions may not be effective in this setting. Given that the reduction of antibiotic resistant infections is a priority of the HHS, The White House, Healthy People 2020, and the World Health Organization, it is necessary to confirm and support the appropriate use of isolation precautions for MDROs with evidence specific to long-term care facilities. Therefore, this dissertation describes the current evidence for and use of isolation precautions in long-term care facilities for MDROs. Further, it offers the most comprehensive descriptions of both isolation precautions use and predictors of MDRO infection in nursing homes (NHs), a specific type of long-term care residential setting. To assist the reader, Chapter 1 will provide background for these studies including context for current infection control and prevention practices in long-term care facilities, the importance of MDRO infections and the need for new evidence regarding isolation precautions in long-term care. It will also discuss the aims and significance of this dissertation in context of a conceptual framework, gaps in the literature and potential to improve clinical practice. Next, Chapters 2 and 3 of this dissertation systematically review the current evidence regarding effectiveness of isolation precautions against MDROs and the cost of infection prevention and control in this setting, respectively. These chapters outline how publications focused on long-term care are lacking in quality and quantity and offer suggestions for improvement in future research. Chapter 4 qualitatively describes decision-making process regarding use of isolation-based infection prevention techniques in NHs, which depends on four key considerations: perceived risk of transmission, conflict with quality of life goals, resource availability and lack of understanding. Chapter 5 builds on this qualitative analysis by quantitatively examining predictors of isolation precautions use for MDRO infection in a large, national dataset. This analysis confirms that isolation is rarely used and there is variation across NHs’ practice. However, NH staff may be tailoring infection prevention and control practice to the needs of specific residents, as would be expected based on the results of the qualitative analysis. Chapter 6 presents an analysis of MDRO infection predictors among elderly NH residents across the U.S. This study confirms concepts associated with MDRO infection in previous studies (e.g., low functionality) and provides more specificity in operationalization of these concepts than has been previously determined (e.g., needing support with locomotion), which can inform future use of isolation precautions in NHs. Finally, Chapter 7 contains a synthesis and discussion of these findings, as well as recommendations for health policy and future research regarding contact isolation precautions against MDROs in NHs.