Pancreatic islet transplantation is a highly promising approach for the treatment of insulin-dependent diabetes mellitus. However, the procedure remains experimental for several reasons, including its low efficiency caused by the early graft loss of transplanted islets. We demonstrate that Gr-1 + CD11b + cells generated by transplantation and their IFN- γ production triggered by V α 14 NKT cells are an essential component and a major cause of early graft loss of pancreatic islet transplants. Gr-1 + CD11b + cells from V α 14 NKT cell–deficient ( J α 281 − / − ) mice failed to produce IFN- γ , resulting in efficient islet graft acceptance. Early graft loss was successfully prevented through the repeated administration of α -galactosylceramide, a specific ligand for V α 14 NKT cells, resulting in dramatically reduced IFN- γ production by Gr-1 + CD11b + cells, as well as V α 14 NKT cells. Our study elucidates, for the first time, the crucial role of Gr-1 + CD11b + cells and the IFN- γ they produce in islet graft rejection and suggests a novel approach to improving transplantation efficiency through the modulation of V α 14 NKT cell function.