Syngeneic pancreatic islets transplanted into the liver or the spleen reverse streptozotocin-induced diabetes in the rat, but allogeneic islets function only briefly and are rejected. Shortly after transplantation, thrombi often form around transplanted tissue, particularly around nonislet tissue that contaminates islet preparations. These thrombi are a source of transient liver injury in recipients of intrahepatic grafts. A few days after transplantation, syngeneic islets injected into the portal vein are found at the periphery of portal tracts in direct contact with periportal hepatocytes, some of which become hypertrophied. Isografts remain situated in the portal tracts for prolonged periods without adverse effect on the surrounding liver. In contrast, allogeneic islets injected into the portal vein are infiltrated by small lymphocytes within 2 days of transplantation and are rapidly destroyed by the host. Syngeneic islets injected into the splenic pulp localize in the sinusoids and, 1 month or more after transplantation, are often surrounded by connective tissue or local collections of hemosiderin-laden macrophages. Allogeneic islets injected into the spleen are rejected with the same intensity and at approximately the same rate as allogeneic islets injected into the portal vein. Transplant rejection leaves no significant lasting morphologic effect on the host liver or spleen.