To examine the immune response to class I—deficient allogeneic tissue, we used β2-microglobulin-deficient mice as graft donors. These mice lack cell surface class I major histocompatibility complex antigen expression. Pancreatic islet allografts from class I-deficient donors survived indefinitely in a majority of fully allogeneic BALB/c recipients. In contrast, host recognition of graft class I antigen was unnecessary for prompt destruction of skin allografts of for autoimmune damage of transplanted pancreatic islet grafts in nonobese diabetic mice. These studies provide evidence that intentional genetic elimination of immunologically relevant donor antigens may prove an effective strategy for preventing allograft rejection.