The majority (65%) of human bacterial infections involve biofilms, a complex heterogeneous community of microorganisms. Staphylococcus aureus causes a broad range of local and systemic infectious diseases including chronic biofilm-associated infections. The high morbidity, mortality and the ever-increasing associated healthcare costs have persuaded scientists to search for a silver bullet. Furthermore, emergence of antibiotic resistance and associated financial justifications have convinced many researchers and pharmaceutical companies that a vaccination approach can be a far more effective preventive approach against staphylococcal infections. As such, many researchers have focused their efforts to develop a vaccine against the free-floating, planktonic, S. aureus. In a new approach, we evaluated the efficacy of a pentavalent vaccine with four biofilm and one planktonic specific recombinant antigen against S. aureus in a murine model of chronic peritoneal abscess. Intraperitoneal challenge with 3x108 CFUs of S. aureus (MRSA M2) in BALB/c mice resulted in 17% (n=2) mortality over 21 days in the vaccinated group and 92% (n=11) in the control group (Fig. 1) (p< 0.001). 80% (n=8) of the survived animals in the vaccinated group cleared the infection. Obtained results confirm the effectiveness of our pentavalent vaccine that targets both planktonic and biofilm-associated proteins in this specific model.