Although intact, viable tumor cells rarely induce a clinically significant immune response in vivo, immunogenicity can be elicited by irradiated tumor cells that protect against subsequent challenge with wild-type intact viable tumor cells. Genetic modification of murine tumor cells, by transfection of cDNAs encoding either cytokines, MHC molecules, or costimulatory molecules, has been capable of inducing antitumor immunity. We and others have previously demonstrated that expression of the B7-1 costimulatory molecule, in either immunogenic or nonimmunogenic tumors, can protect against subsequent challenge with wild-type tumor cells. In this work, using a murine model of acute myeloid leukemia, we demonstrate that the B7-1 costimulatory molecule is superior to the B7-2 molecule in its capacity to protect against wild-type tumor challenge and eradicate minimal residual disease. These results provide compelling evidence that the B7-1 and B7-2 costimulatory signals are functionally distinct, thus resulting in clinically significant differences in the induction of antitumor immunity in vivo.