Cancer immunoediting, the process by which the immune system controls tumor growth and shapes tumor immunogenicity, consists of 3 stages: elimination, equilibrium, and escape. The molecular mechanisms that underlie the equilibrium phase, during which the immune system maintains tumor dormancy, remain incompletely defined. Here, we investigated the length of the equilibrium phase during immune control of methycholanthrene (MCA)-induced or p53 mutant cancers and showed the critical and opposing roles of interleukin (IL)-23 and IL-12 in maintaining cancer cells in a state of immune-mediated dormancy. Inhibition of IL-23p19 was shown to reduce the malignant potential of lesions established by MCA inoculation, whereas inhibition of IL-12/23p40 enhanced tumor outgrowth. Furthermore, agonistic anti-CD40 antibody treatment mimicked the effects of anti-IL-23p19 monoclonal antibody treatment. Other cytokines such as IL-4, IL-17, TNF, and IFNαβ, which are known to play important roles either in MCA tumorigenesis or in the elimination phase of cancer immunoediting, did not play critical roles in maintaining the equilibrium phase. Taken together, our findings show opposing roles for IL-23 and IL-12 in determining the outgrowth versus dormancy of occult neoplasia and suggest a potential long-term danger in using IL-12/23p40 antibodies for treating human autoimmune inflammatory disorders. Cancer Res; 72(16); 3987–96. ©2012 AACR.