The injury of transplanted islets may occur by both autoimmune and alloimmune processes directed against MHC targets. To examine the role of MHC class I in islet graft injury, we transplanted syngeneic and allogeneic beta2-microglobulin-deficient islets into diabetic nonobese diabetic (NOD) mice. Loss of graft function was observed within 14 days using allogeneic C57BL/6 and BALB/c MHC class I deficient as well as wild-type MHC class I-bearing NOD donor islets. However, islets isolated from MHC class I-deficient NOD mice (NOD-B2 m-/-) survived indefinitely when transplanted under the kidney capsule of diabetic NOD recipients. Transplanted NOD-B2 m-/- islets were surrounded by a nondestructive periinsular infiltrate that expressed interleukin-4 in addition to interferon-gamma. These studies demonstrate the primary role of MHC class I molecules in causing autoimmune destruction or recurrent diabetes in transplanted islets.