Abstract Background: The long-term objective of the “Povidone-iodine to stop Access related INfections and Transmission of Staphylococcus aureus (PAINTS)” proposal is to decrease rates of healthcare- associated infections that occur outside of the hospital (i.e., community-onset infections). Recent data from the Centers for Disease Control and Prevention (CDC) demonstrated that 83% of methicillin- resistant Staphylococcus aureus (MRSA) bloodstream infections are community-onset. Hemodialysis patients are at high-risk for community-onset bloodstream infections, particularly S. aureus access- related bloodstream infections (ARBSI). These infections cause increased morbidity and mortality. Nasal povidone-iodine decolonization is a novel intervention that can potentially prevent S. aureus ARBSI in this patient population. Specific Aims: Aim 1: Assess whether nasal povidone-iodine decolonization reduces infections among hemodialysis patients using a multicenter, stepped-wedge cluster randomized trial. Primary outcome: S. aureus ARBSI. Secondary outcomes: Other S. aureus dialysis-associated infections as defined by the CDC National Healthcare Safety Network, ARBSI caused by pathogens other than S. aureus, all dialysis-associated infections caused by all pathogens, and S. aureus colonization and transmission. Aim 2: Evaluate patient satisfaction with nasal povidone- iodine decolonization, assess its role in patient activation, and assess barriers and facilitators to implementation using patient surveys. Aim 3: Examine healthcare worker satisfaction with implementation of nasal povidone-iodine decolonization and assess barriers and facilitators to the process via qualitative interviews and site visits. Research Design: We aim to perform a randomized stepped wedge study among 16 hemodialysis units affiliated with 5 geographically diverse healthcare centers to evaluate whether nasal povidone-iodine will reduce rates of S. aureus ARBSI among hemodialysis patients. These hemodialysis units represent both rural and inner-city patients who receive chronic care (AHRQ priority populations). We will survey all patients and qualitatively interview healthcare workers to assess the acceptability and feasibility of this intervention, as well as barriers and facilitators to implementation. We will test patients' noses for S. aureus colonization to determine whether nasal povidone-iodine decreases S. aureus colonization and S. aureus transmission. The sites that will participate in this study (University of Iowa, University of Illinois, University of Pennsylvania, Washington University, Emory Healthcare) have a good history of collaboration. Relevance: This study will help AHRQ address its goal to “build the evidence for fighting antibiotic resistance in the ambulatory setting,” and help meet the National Action Plan to Prevent Healthcare-Associated Infections recommendation that hemodialysis centers aim to improve ARBSI rates.