To test whether alloimmunization with H-2 or/and non-H-2 different normal tissues may increase the immunity to syngeneic tumors, groups of BALB/c (H-2d) mice were immunized with a series of allogeneic lymphoid cells and then challenged i.p. with syngeneic lymphoma cells. The outgrowth of otherwise lethal doses of the Moloney virus-induced lymphoma YC8 and of its clones was inhibited in BALB/c mice immune to DBA/2 (H-2d), C3Hf (H-2k), C3H.SW (H-2b), C3H.OH (H-2o2) and to B10 background tissues but not in mice immunized to A/He, BALB.K (H-2k) or BALB.B (H-2b) normal tissues. Anti-YC8 effect was also induced by immunizing BALB/c recipients with a pool of five different allogeneic cell lines which included C3Hf, C57BL/6J (H-2b), N:NIH (H-2q), B10.M (H-2f), and DBA/2 lymphoid cells. No growth inhibition of other BALB/c lymphomas induced by Moloney virus (LSTRA), X-rays (RL♂I) or urethane (UR-I) was evident in alloimmune mice. In vivo transfer of growth inhibition of YC8 was obtained with BALB/c anti-B10.D2 peritoneal exudate cells in a Winn assay. The ability of these alloimmune lymphoid cells to delay significantly the survival time of BALB/c mice injected with the mixture of immune cell and YC8 cells was abrogated by anti-Thy 1.2 plus C' treatment. In addition, nu/nu BALB/c mice were unable to develop resistance to YC8 outgrowth after alloimmunization. The results of this study show that: (1) syngeneic growth of a lymphoma can be prevented by alloimmunization with normal cells; (2) this cross-reaction involved non-H-2 antigens; (3) the phenomenon appeared to be mediated by T cells.