The ability of TAP1-/-, beta2m-/-, and TAP1/beta2m-/- mice to mount rejection responses against allogeneic, syngeneic, and MHC class I-deficient tumor grafts was examined. The results demonstrate a potent ability of TAP1-/- and beta2m-/- as well as TAP1/beta2m-/- mice to reject allogeneic tumors. In contrast to published data, rejection of syngeneic MHC class I-expressing tumors was also observed. This response was specific for the MHC class I-deficient mice, since wild-type mice did not reject syngeneic MHC class I-positive tumors under identical experimental conditions. The rejection response of syngeneic tumors required preimmunization of the mice and was MHC class I specific at the level of priming as well as at the level of the tumor target. Finally, MHC class I-deficient tumor grafts were accepted in MHC class I-deficient mice while similar grafts were rejected in wild-type mice. In summary, while MHC class I-deficient mice have retained a capacity to reject allogeneic tumors. they have gained an ability to reject syngeneic MHC class I-positive tumors and lost the ability to reject MHC class I-negative tumors. The present results are discussed in relation to the role of MHC class I molecules in selecting functional CD8+ T and NK cell repertoires, and the development of cell-mediated immunity.