Characterize the clinical and molecular epidemiology of new methicillin-resistant Staphylococcus aureus (MRSA) acquisitions at nasal and extranasal sites among high-risk nursing home (NH) residents. Multicenter prospective observational study. Six NHs in southeast Michigan. A total of 120 NH residents with an indwelling device (feeding tube and/or urinary catheter). Active surveillance cultures from the nares, oropharynx, groin, perianal area, wounds (if present), and device insertion site(s) were collected upon enrollment, at day 14, and monthly thereafter. Pulsed-field gel electrophoresis and polymerase chain reaction for SCCmec, agr, and Panton-Valentine leukocidin were performed. Of 120 participants observed for 16,290 device-days, 50 acquired MRSA (78% transiently, 22% persistently). New MRSA acquisitions were common in extranasal sites, particularly at device insertion, groin, and perianal areas (27%, 23%, and 17.6% of all acquisitions, respectively). Screening extranasal sites greatly increases the detection of MRSA colonization (100% of persistent carriers and 97.4% of transient carriers detected with nares, groin, perianal, and device site sampling vs 54.5% and 25.6%, respectively, for nares samples alone). Colonization at suprapubic urinary catheter sites generally persisted. Healthcare-associated MRSA (USA100 and USA100 variants) were the dominant strains (79.3% of all new acquisition isolates). Strain diversity was more common in transient carriers, including acquisition of USA500 and USA300 strains. Indwelling device insertion sites as well as the groin and perianal area are important sites of new MRSA acquisitions in NH residents and play a role in the persistency of MRSA carriage. Clonal types differ among persistent and transient colonizers.