Tissue-specific differences in immunogenicity were demonstrated following allotransplantation across the same minor histocompatibility barrier (BALB/c----DBA/2). In contrast to the high immunogenicity of fetal pancreas and skin, isolated islets, fetal proislets, and thyroid were weakly immunogenic. These tissue-specific effects were not related to the presence of tissue-specific antigens or the absence of recognizable minor alloantigens from the less immunogenic tissues. There was a strong correlation between tissues that were highly immunogenic and those that contained rich populations of donor leukocytes. The survival of fetal pancreas allografts was significantly improved by pretreating the donor tissue in high-oxygen organ culture and by the preparation of fetal proislets. Using other MHC-compatible strain combinations (B10.D2----BALB/c; BALB/c----B10.D2; C3H.SW----C57/10J) strain-specific effects were observed in the immunogenicity of thyroid allografts. In two of three strain combinations (B10.D2----BALB/c; BALB/c----B10.D2), pretreatment of the donor tissue with cyclophosphamide and organ culture prior to grafting significantly improved graft survival. These findings suggest that donor passenger leukocytes may play an important role in determining the immunogenicity of MHC-compatible allografts.