Methicillin-resistant S. aureus emerged in recent decades to become a leading cause of infection worldwide. Colonization with MRSA predisposes to infection and facilitates transmission of the pathogen; however, available regimens are ineffective at preventing MRSA colonization. Studies of human nasal flora suggest that resident bacteria play a critical role in limiting S. aureus growth, and prompted us to query whether application of commensal resident bacteria could prevent nasal colonization with MRSA. We established a murine model system to study this question, and showed that mice nasally pre-colonized with S. epidermidis became more resistant to colonization with MRSA. Our study suggests that application of commensal bacteria with antibiotics could represent a more effective strategy to prevent MRSA colonization.