Although Yersinia enterocolitica is extracellularly located in infected tissues, a specific T cell response is required to overcome infection. Recent work implicated that in contrast to Yersinia-susceptible BALB/c mice, C57BL/6 mice are Yersinia resistant due to the rapid development of a Yersinia-specific Th1 T cell response. This study focused on the role of IL-12 in Y. enterocolitica infections in both mouse strains. We found that C57BL/6 and BALB/c mice produced comparable quantities of IL-12 mRNA after Y. enterocolitica infection. Likewise, Yersinia-infected bone marrow macrophages from both mouse strains produced equal quantities of IL-12. Administration of neutralizing anti-IL-12 Abs abrogated resistance against yersiniae in either strain. In addition, administration of rIL-12 rendered BALB/c mice resistant to yersiniae, while this treatment was toxic to C57BL/6 mice. IL-12-mediated protection was partially dependent on IFN-gamma. Spleen cells from both strains of mice produced Yersinia-triggered IFN-gamma in an IL-12-dependent manner, although those from BALB/c mice produced 10-fold lesser quantities. Administration of rIL-12 in vivo increased Yersinia-induced IFN-gamma production by BALB/c spleen cells in vitro, but decreased IFN-gamma production by spleen cells from C57BL/6 mice. IL-10 was antagonistic to IL-12 only in BALB/c mice and inhibited Yersinia-triggered IFN-gamma production. In vivo depletion experiments revealed that IL-12 accounts for Yersinia-induced IFN-gamma production by both NK cells and CD4+ T cells, the latter of which are an essential source of IFN-gamma r while NK cell-derived IFN-gamma production can be compensated by other cells. In contrast to that in the spleen, IL-12 plays a minor role in protection against yersiniae in Peyer's patches after orogastric infection. In summary, our data suggest that IL-12 is rapidly induced by Y. enterocolitica infection and required for IFN-gamma production by NK cells as well by CD4+ T cells. Although BALB/c and C57BL/6 mice produced comparable quantities of IL-12, IFN-gamma production, and thus resistance to yersiniae, can be increased by exogenous IL-12 only in BALB/c, not in C57BL/6, mice.