Uncertainty persists about risk factors for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections in Europe and the long-term efficacy of decolonization strategies. To evaluate risk factors for CA-MRSA in Geneva, Switzerland, a hospital-based, retrospective case-control study of 26 patients with CA-MRSA infection and 60 control patients was performed. To evaluate the long-term effect of a systematic decolonization strategy (with and without concomitant systemic antibiotic therapy) for CA-MRSA patients, a prospective cohort study of 79 patients with Panton-Valentine leukocidin-producing CA-MRSA isolates was conducted. Nationality other than European Union or Swiss (adjusted OR 6.09; 95% CI 1.07-34.65) and absence of healthcare contact (adjusted OR 0.11, 95% CI 0.02-0.59) were independent predictors of CA-MRSA infection. Forty-five cases were followed (median, 22 months) to assess the long-term efficacy of the decolonization strategy; 39/45 (86.7%) had no clinical relapse and were MRSA-negative at their last follow-up, whereas six remained MRSA-positive. Five of these six cases belonged to a family cluster. Decolonization rates were similar between infected patients and asymptomatic carriers (92.6% vs. 77.8%, p = 0.20). This study shows a lack of readily modifiable risk factors for CA-MRSA infection in this population, and suggests the potential usefulness of conducting decolonization procedures in a setting with sporadic CA-MRSA infection. Further studies are needed to elucidate the role of migration as a factor contributing to the emergence of CA-MRSA in Europe.