ABSTRACTStaphylococcus aureusis a major cause of morbidity and mortality worldwide.S. aureuscolonizes 20 to 80% of humans at any one time and causes a variety of illnesses. Strains that are resistant to common antibiotics further complicate management.S. aureusvaccine development has been unsuccessful so far, largely due to the incomplete understanding of the mechanisms of protection against this pathogen. Here, we studied the role of different aspects of adaptive immunity induced by anS. aureusvaccine in protection againstS. aureusbacteremia, dermonecrosis, skin abscess, and gastrointestinal (GI) colonization. We show that, depending on the challenge model, the contributions of vaccine-inducedS. aureus-specific antibody and Th1 and Th17 responses to protection are different: antibodies play a major role in reducing mortality duringS. aureusbacteremia, whereas Th1 or Th17 responses are essential for prevention ofS. aureusskin abscesses and the clearance of bacteria from the GI tract. Both antibody- and T-cell-mediated mechanisms contribute to prevention ofS. aureusdermonecrosis. Engagement of all three immune pathways results in the most robust protection under each pathological condition. Therefore, our results suggest that eliciting multipronged humoral and cellular responses toS. aureusantigens may be critical to achieve effective and comprehensive immune defense against this pathogen.IMPORTANCES. aureusis a leading cause of healthcare- and community-associated bacterial infections.S. aureuscauses various illnesses, including bacteremia, meningitis, endocarditis, pneumonia, osteomyelitis, sepsis, and skin and soft tissue infections.S. aureuscolonizes between 20 and 80% of humans; carriers are at increased risk for infection and transmission to others. The spread of multidrug-resistant strains limits antibiotic treatment options. Vaccine development againstS. aureushas been unsuccessful to date, likely due to an inadequate understanding about the mechanisms of immune defense against this pathogen. The significance of our work is in illustrating the necessity of generating multipronged B-cell, Th1-, and Th17-mediated responses toS. aureusantigens in conferring enhanced and broad protection againstS. aureusinvasive infection, skin and soft tissue infection, and mucosal colonization. Our work thus, provides important insights for future vaccine development against this pathogen.