Staphylococcus epidermidis is a frequent cause of infections associated with foreign bodies and indwelling medical devices. The bacteria are capable of surviving antibiotic treatment through encapsulation into biofilms. RNAIII-inhibiting peptide (RIP) is a heptapeptide that inhibits S. aureus pathogenesis by disrupting quorum-sensing mechanisms. In this study, RIP inhibited drug-resistant S. epidermidis biofilm formation through a mechanism similar to that evidenced for S. aureus. RIP is synergistic with antibiotics in eliminating 100% of graft-associated in vivo S. epidermidis infections, which suggests that RIP may be used to coat medical devices to prevent staphylococcal infections. Disruption of cell-cell communication can prevent infections associated with antibiotic-resistant strains.