To evaluate the fate of retinal pigment epithelial cell (RPE) allografts in the subretinal space. Transplantation was performed in Royal College of Surgeons (RCS) rats. Two rat strains, BD IX and LEJ, which have incompatible major histocompatibility complex (MHC) haplotypes, were selected as healthy RPE donors. Transplantation was performed when recipients were 19 to 21 days old. Host systemic immunity was enhanced by challenge with donor spleen cells 2 weeks after RPE transplantation. Control subjects were administered injections of saline or host spleen cells. The animals were killed at 3 or 5 months of age. The extent of photoreceptor rescue was determined by counting the maximum layers of surviving photoreceptor nuclei in histologic sections. Reverse transcription-polymerase chain reaction analysis of the grafts was performed with host-and donor-specific primers. Despite the absence of acute immune rejection, chronic rejection occurred and was evidenced by an increased loss of photoreceptor cells in immunologically challenged RCS rats. Grafts with disparity at MHC class I and class II lost their ability to rescue photoreceptor cells more readily than did grafts with disparity at MHC class II alone. Furthermore, the donor RPE cells that were normally MHC class II-negative expressed MHC class II mRNA in the subretinal space after transplantation. Systemic immunity appeared to exert a slow but significant influence in the subretinal space. Therefore, in planning future trials involving human subjects, the immunologically privileged status of the subretinal space should be regarded as imperfect.