We have investigated the importance of endogenously produced IL-12 in innate and adaptive immunity to tumor transplants. The immunogenic lymphoma RMA and its TAP-deficient variant RMA-S were tested for rejection responses by normal and IL-12-deficient mice. IL-12 was crucial for the immunity induced by one immunization with irradiated RMA cells, as well as for in vivo priming of a CTL response in mixed lymphocyte tumor cultures against this MHC class I-expressing tumor. The defective in vivo response could be overcome by multiple immunizations. In further studies of in vitro CTL responses, we found that IL-12 production from either the antigen-pulsed dendritic cells or from host cells was necessary to obtain strong CTL responses. In the complete absence of IL-12, no or only very weak responses could be detected. NK cell-mediated innate resistance, as assessed in non-immunized mice inoculated with a threshold dose of RMA-S cells, also required IL-12. However, NK cells with reduced activity were present in IL-12-deficient mice and contributed to innate resistance, as demonstrated with lower cell dose challenges. In conclusion, IL-12 is required for optimal adaptive and innate responses against tumors.