Staphylococcus aureus is an opportunistic pathogen that causes numerous debilitating infections such as pneumonia, endocarditis, bacteremia, complicated skin soft tissue infections. These infections are associated to high level of morbidity and mortality especially in immune-compromised patients. Antibiotic resistance has reduced treatment options and underscores a need for alternative antibacterial treatment strategies. The increase incidence of multiple drug resistant isolates raises for the need of alternative therapies such as immuno-therapy. We have developed three human monoclonal antibodies (mAbs) against Staphylococcus aureus secreted alpha toxin (MEDI4893), and the four main bi-component leukotoxins (SAN481) as well as surface expressed Clumping Factor A (SAR114), six virulence factors exerting different activities on the host. AT and the bi-components leukotoxins (LukSF, LukED, HlgAB and HlCB) are pore-forming toxins that causes immune dysregulation, cell death and promotes bacterial dissemination, whereas ClfA is a fibrinogen binding protein that promotes biofilm formation, bacterial agglutination and complement evasion. MAb combination showed broad strain coverage in multiple animal models through complementary mechanism of action such as toxin neutralization, inhibition of bacteria agglutination and opsonophagocytic killing. MEDI4893 prophylaxis also demonstrated efficacy in a S. aureus + Gram-negative mixed lung infection model. Together our data hold some promise as an alternative therapy for the prevention of S. aureus diseases.