The proportion of methicillin-resistant Staphylococcus aureus (MRSA) in Denmark has been below 1% for more than 30 years. However, a marked increase in community-onset MRSA (CO-MRSA) started in 2002. To identify possible risk factors for CO-MRSA infections, a nationwide case-control study was conducted in 2004. Cases (34) were patients with CO-MRSA infections; controls (87) were patients with community-onset methicillin-sensitive S. aureus infections (CO-MSSA). Demographic and clinical data and exposures to possible risk factors during the last 24 months were collected with a structured telephone-administered questionnaire. Skin and soft tissue were the predominant sites of infection, both for cases (68%) and for controls (60%). A large proportion of cases (26%) and controls (38%) had an underlying skin disease. The majority of cases (76%) and controls (61%) had received antibiotics within the last 6 months, and 51% and 31%, respectively, had been hospitalized within the previous year. In a multivariate analysis, non-Danish origin, defined as being from or having parents from outside Denmark, was the only independent risk factor for CO-MRSA infection (OR 30.5, 95% CI 3.6-257.3). Prior hospitalization for >7 days within the previous 6 months tended to be associated with CO-MRSA infection (OR 5.7, 95% CI 0.9-36.4). The predominant MRSA clones found in this study were CC80 (26%), CC8 (24%) and CC5 (18%). Resistance to three or more antimicrobial drug classes was seen in 47% of CO-MRSA isolates. Panton-Valentine leukocidin was found in 47% of CO-MRSA isolates. Apart from a non-Danish origin, CO-MRSA shared the same risk factors as CO-MSSA, which makes control a challenge.