To examine the pathogenesis of USA300 MRSA infection in long-term care residents, we performed a retrospective cohort study of 1691 adult residents of two extended-care facilities from 2003 to 2007 to assess whether the risk of subsequent MRSA infection is higher in USA300 MRSA-colonized residents compared to non-colonized residents or non-USA300 MRSA colonized residents. Six per cent of residents were colonized with USA300 MRSA; 12% of residents were colonized with non-USA300 MRSA; and 101 residents developed MRSA infection. The risk of infection was twofold higher in residents colonized with USA300 MRSA compared to residents not colonized with MRSA [adjusted hazard ratio 2.3, 95% confidence interval (CI) 1.1–4.5]. The risk of infection in USA300 MRSA-colonized residents was similar to USA300 MRSA non-colonized residents (relative risk 1.1, 95% CI 0.5–2.3). Our findings show that colonization with USA300 MRSA increases the risk of MRSA infection suggesting a similar pathogenesis.