Pancreatectomized dogs received intrasplenic auto-transplants or allotransplants of unpurified islets prepared from the pancreata of unrelated outbred dogs, by a standard collagenase ductal perfusion method. Allograft immunosuppression consisted of tapering azathioprine-prednisone (AP), low level cyclosporine (CsA, through whole blood high-pressure liquid chromatography (HPLC) level 300–600 μg/L), or high CsA (600–1000 μg/L). While AP and low CsA failed to delay rejection, high CsA achieved prolonged (>100 days) graft function in 5 of 12 dogs, with a median duration of 85.5 days. (P<.01 vs. AP and low CsA). While no interference with islet engraftment was seen in CsA-treated dogs, late graft failure (>30 days) was seen in 3 of 6 CsA autografts and 5 of 12 high CsA allografts. CsA at whole-blood HPLC levels of 600–1000 μg/L can achieve prolonged normoglycemia in pancreatectomized canine recipients of islet allografts. The effects of such doses of CsA on islet function may be substantial.