Interleukin-12 (IL-12) is one of the first cytokines produced by macrophages, key mediators of innate resistance, during the host’s immune response to infections. Therefore, in this study we propose that IL-12 has an important role in the early phase of the immune response to Mycobacterium bovis BCG. IL-12 has been shown to enhance the maturation of protective Th1 cells and gamma interferon (IFN-γ) production during mycobacterial infection. Therefore, it may play a crucial role during the immune phase of infection as well. To examine the role of IL-12 in both the innate and the immune phase of infection, we compared BCG-resistant mice, B10.A (Bcg^r), to the susceptible congenic strain B10.A (Bcg^s) following administration of a blocking monoclonal antibody to IL-12 (10F6). Anti-IL-12-treated susceptible animals exhibited a two- to threefold increase in spleen CFU by day 21. In contrast, anti-IL-12 treatment had little or no effect on the response of the genetically resistant animals to infection. The B10.A (Bcg^r) but not the B10.A (Bcg^s) mice had an increase in IFN-γ mRNA relative to baseline levels as early as day 1 of infection irrespective of anti-IL-12 treatment. By day 14, B10.A (Bcg^r) mice showed a decrease in IFN-γ mRNA while the B10.A (Bcg^s) mice showed a significant increase in IFN-γ mRNA levels. Thus, during BCG infection, the B10.A (Bcg^r) mice mount an early IFN-γ response against BCG whereas the B10.A (Bcg^s) mice have a delayed IFN-γ response correlating with their genetic permissiveness expressed as an increased mycobacterial load by day 21. Overall, our data demonstrate that the inherent resistance of B10.A (Bcg^r) mice to mycobacteria does not depend on optimal levels of IL-12 to maintain effective control of the bacteria, whereas IL-12 is important for the susceptible animals’ response to BCG during the peak of infection.