Patients with community-onset methicillin-resistant (CO-MRSA) infections contribute to MRSA contamination of the home environment, and may be re-exposed to MRSA strains from this reservoir. This study evaluates One Health risk factors that focus on the relationship between humans, animals and the environment for increased prevalence of multiple antimicrobial resistant MRSA in the home environment. During a trial of patients with CO-MRSA infection, MRSA was isolated from the household environment at baseline and three months later, following randomization of patients and household members to mupirocin-based decolonization therapy or education control. Up to two environmental MRSA isolates per visit were tested. MRSA isolates were identified in 68% (65/95) of homes at baseline (=104 isolates) and 51% (33/65) of homes three months later (=56 isolates). Rates of MDR were 61% at baseline and 55% at the three-month visit. At baseline, 100% (14/14) of MRSA isolates from rural homes were MDR. While antimicrobial use in humans or pets was associated with an increased risk for the isolation of MDR MRSA from the environment, clindamycin use was not associated risk for isolation of MDR MRSA. Two (5%) of 39 homes that were randomized to mupirocin treatment, but none of the control families, had incident low-level mupirocin resistant MRSA isolated at three months. Among patients recently treated for a CO-MRSA infection, MRSA and MDR MRSA were common contaminants in the home environment. This study contributes to evidence that occupant use of antimicrobial drugs--except clindamycin--is associated with MDR MRSA in the home environmental reservoir. MRSA is a common bacterial agent implicated in skin and soft tissue infections (SSTIs) in both community and healthcare settings. Patients with CO-MRSA infections contribute to MRSA contamination and may be re-exposed to MRSA strains from these reservoirs. People interact with natural and built environments, therefore understanding the relationships between humans and animals as well as characteristics of environmental reservoirs is important to advance strategies to combat antimicrobial resistance. Household interactions may influence the frequency and duration of exposure, which in turn may impact the duration of MRSA colonization or probability for recurrent colonization and infection. Therefore, MRSA contamination of the home environment may contribute to human and animal recolonization and decolonization treatment failure. The aim of this study was to evaluate One Health risk factors that may be amenable to intervention and may influence the recovery of MDR and mupR resistance in CO-MRSA isolates.