Staphylococcus aureus is a very important human pathogen that causes significant morbidity and mortality worldwide. Several vaccine clinical trials based on generating antibody against staphylococcal surface polysaccharides or proteins have been unsuccessful. A killed whole cell lysate preparation (SaWCA) was made by lysing a USA 300 strain with lysostaphin followed by sonication and harvest of the supernatant fraction. Immunization with SaWCA and cholera toxin (CT) generated robust IL-17A but relatively modest antibody responses, and provided protection in the skin abscess but not in the dermonecrosis or invasive infection model. In contrast, parenteral immunization with SaWCA and alum produced robust antibody and IL-17A responses and protected mice in all three models. Sera generated after immunization with SaWCA had measurable antibodies directed against six tested conserved surface proteins, and promoted opsonophagocytosis activity (OPA) against two S. aureus strains. Passive transfer of SaWCA-immune serum protected mice against dermonecrosis and invasive infection but provided no demonstrable effect against skin abscesses, suggesting that antibodies alone may not be sufficient for protection in this model. Thus, immunization with a SA lysate preparation generates potent antibody and T cell responses, and confers protection in systemic and cutaneous staphylococcal infection models.