Survival of pancreatic islet cells transplanted into the subretinal space in rat eyes was studied in relation with apoptosis of infiltrating lymphocytes. Islets isolated from inbred DA rats were transplanted into the subretinal space of fully MHC-mismatched Lewis rats. Syngeneic subretinal transplants and allogeneic subretinal transplants from Sprague-Dawley (SD) rats were performed as controls. From 7 to 60 days after transplantation, immunoperoxidase staining for insulin, glucagon, CD4, CD8, and interleukin (IL)-2, and evaluation of apoptosis using nick-end labeling (TUNEL) were performed. Fully MHC-mismatched grafts were rejected by day 14, showing massive infiltration by CD4+, CD8+, and IL-2+ lymphocytes. Syngeneic transplants and allografts in SD rats survived up to 60 days without appreciable lymphocytic infiltration. Endocrine cells were the major component of surviving transplanted tissue. No difference in distribution of TUNEL+ cells was seen between syngeneic transplants and subretinal allografts in SD rats on day 60. A few TUNEL+ CD8+ lymphocytes were found in rejected MHC-mismatched transplants, but apoptotic lymphocytes were not seen in surviving or syngeneic grafts. Pancreatic islet survival in the subretinal space is MHC dependent. Accumulation of infiltrating lymphocytes may be suppressed by a modified immune response.