The spleen has been examined as a possible site for transplantation of rat islets into diabetic mice. Marked prolongation of islet xenograft survival in the spleen can be achieved with in vitro culture (24 C) and a single injection of either rabbit antiserum to mouse lymphocytes (MALS) alone or MALS and rabbit antiserum to rat lymphocytes (RALS) into the recipients. The percentage of survival of intrasplenic xenografts at 100 days was 16%, as compared with 70% when rat islet xenografts were transplanted via the portal vein. Further improvement in pretreatment regimens will be needed before the spleen can be used as an effective site for possible future islet allograft or xenograft transplants in man.