The Caf1 and LcrV sub-unit vaccine for plague has been shown to be highly protective against challenge with virulent Yersinia pestis in a mouse model. Production of large amounts of IgG1 in response to the vaccine correlates with protection against aerosol and parenteral infection. In this study the effect of genetic mutation in the immune system on protection was addressed. Stat 6(-/-) mice which are unable to utilise the type 2 cytokines IL-4 and IL-13 and so should have reduced IgG1 responses were utilised in order to determine whether an immune system biased towards the type 1 axis could mount an effective response to the vaccine. Conversely in the Stat 4(-/-) mouse model, IL-12 and interferon-gamma-mediated immune mechanisms are inactive and the immune response should be biased towards the type 2 axis. Serum antibody responses to vaccination in both the knockout strains and their wild type controls revealed little difference in levels of IgG and isotype profiles. Elispot analysis of cytokine production at the single cell level did however reveal a functional defect in the Stat 4(-/-) mice which had low levels of IFN-gamma producing cells. Following virulent challenge, the Stat 6(-/-) mice showed high levels of protection, while the Stat 4(-/-) mice were poorly protected, indicating a fundamental defect in their immune systems which could not be overcome even by the passive transfer of CD4(+) cells from immunised BALB/c donors. It appears therefore that type 1 immune mechanisms, activated following Stat 4 phosphorylation, are essential in protection against plague.