Staphylococcus aureus remains an important human and animal pathogen. Its pathogenicity is determined in part by expression of the Spa-immune subversion protein, neutralising the activity of which provides partial protection in murine models, as does experimental infection with live S. aureus with Spa gene deletions followed by antibiotic-mediated cure in mice. Together, these data raise the question of whether Spa mutant S. aureus might represent a viable vaccine. Here, we find that gamma-irradiated S. aureus strains, both wild-type and null mutant of spa , are immunogenic in mice when administered intramuscularly, eliciting large amounts of anti- S. aureus antibodies, as judged by whole-cell immunoassay on fixed microorganisms. We used an intravenous challenge system to assess vaccine efficacy, the sensitivity of which was increased by studying renal bacterial concentrations in both kidneys. Despite this, protection from intravenous challenge was not observed (mean difference between vaccinated and unvaccinated mice 0.27 log 10 with 95% confidence interval −0.922 to 1.467). Surprisingly, antibody responses elicited against a panel of protective cell surface proteins were very low, indicating that most antibody induced is not protective. Additionally, these data suggest a limited role for irradiated wild-type or spa mutant S. aureus as vaccines.