Diabetic A.TL and A.TH mice, congenic inbred strains differing only in the I and S (non-K, non-D) regions of the major histocompatibility (H-2) complex, received intrasplenic allogeneic and isogeneic pancreatic islet transplants. The isografts were uniformly accepted, while approximately 60% of the recipients receiving allografts rejected the islets, most within 4 weeks of transplantation. With either strain the animals accepting the allografts had higher blood glucose values than normal mice or isografted recipients. After a minimum of 13 weeks of nearly normal glucose levels, successfully alografted mice received skin grafts and spleen cells. None of the A.TH recipients rejected the A.TL islets, but two of four A.TL recipients of A.TH islets became diabetic after the skin grafts. These observations suggest a variable response to islets transplanted across this isolated difference of the H-2 complex. Furthermore, allografted islets resisting rejection did not provide normal glucose levels in the recipients.