Immunization with trinitrophenyl (TNP)-derivatized allogeneic lymphoma cells resulted in significant immunity to poorly immunogenic syngeneic lymphoma cells. Neither TNP-treated nor X-irradiated syngeneic lymphoma cells were immunogenic under similar experimental conditions. Immunization with untreated allogeneic lymphoma cells produced only minimal levels of resistance to challenge with syngeneic lymphoma cells. The complete set of antigens responsible for the immunity was carried exclusively on transformed lymphocytes because allogeneic TNP-derivatized lymph node and thymus cells also did not immunize. The immunity was transferred to nonimmune inbred BALB/c and A/J mice by spleen cells from immune donors. The Winn assay was used to measure the antilymphoma immunity in vivo. When immune spleen cell-lymphoma mixtures were inoculated sc at a ratio of 1,000:1, nonimmune mice were completely protected. Reactivity of immune lymphocytes to syngeneic lymphoma cells was also demonstrated in vitro by the 51Cr-release method. Immunization with TNP-derivatized allogeneic lymphoma cells resulted in measurable immune resistance to inocula of viable syngeneic tumor cells in excess of 100 times the tumorigenic dose. Induction of immunity to syngeneic lymphoma cells strictly required that the immunizing cells be histoincompatible at the major H-2 locus and possess tumor-specific antigen(s). Maximum immune sensitivity was observed only after chemical modification of the immunizing allogeneic lymphoma cells.