The dimeric cytokine IL‐12 is important in the control of various infections but also contributes to the pathology of certain diseases making it a potential target for therapy. However, its specific inhibition with antibodies is complicated by the fact that its two subunits are present in other cytokines: p40 in IL‐23 and p35 in IL‐35. This has led to erroneous conclusions like the alleged implication of IL‐12 in experimental autoimmune encephalomyelitis (EAE). Here, we report the development of a mouse anti‐mouse IL‐12 vaccine and the production of monoclonal antibodies (mAbs) that do not react with p40 or p35 (in IL‐35) but specifically recognize and functionally inhibit the IL‐12 heterodimer. Using one of these mAbs, MM12A1.6, that strongly inhibited IFN‐γ production and LPS‐induced septic shock after viral infection, we demonstrate the critical role played by IL‐12 in the rejection of male skin graft by female C57BL/6 syngeneic recipients and in the clearance of an immunogenic mastocytoma tumor variant by DBA/2 mice, but not in a parent to F1 immune aggression model nor in MOG‐induced EAE, which was clearly prevented by anti‐p40 mAb C17.8. Given this selective inhibition of IL‐12, these mAbs provide new options for reassessing IL‐12 function in vivo.