AbstractThis report describes model systems which show low primaryin vitrosyngeneic cytotoxic responses to a Moloney‐induced YAC tumor (syngeneic in A mice) and a Rauscher‐induced RBL5 tumor (syngeneic in C57BL/6 mice) and examines different approaches to overcome these defects.Two major findings were obtained: (a) spleen cells from A mice, injected with tumor cells from anin vitrotumor line YAC‐1, derived from YACL, could generate a significant syngeneic cytotoxic response. In contrast, spleen cells from A mice injected with tumor cells from thein vivotumor line failed to generate a syngeneic cytotoxic response. Thus, tumor cells from thein vitroline were more immunogeneic that those from thein vivoline. (b) Spleen cells from A mice which were injected with the crossreactive allogeneic tumor RBL5, could generate significant cytotoxic responses to the syngeneic tumors YAC and YAC‐1. Similarly, spleen cells from C57BL/6 mice injected with the cross‐reactive allogeneic tumor YAC‐1, could generate a significant cytotoxic response to the syngeneic tumor RBL5. Thus, cross‐reactive allogeneic tumors could stimulate syngeneic cytotoxicity. The theoretical and the practical implications of these studies