An instant blood-mediated inflammatory reaction (IBMIR) is elicited when islets come in contact with blood after intraportal transplantation. In contrast, endothelial cells (EC) readily tolerate contact with blood. A conceivable strategy to overcome IBMIR would be to create composite islet-EC grafts. Human islets were co-cultured with primary human aortic endothelial cells (HAEC) for 2–7 days to obtain 50–90% coverage. HAEC-coated islets were exposed to ABO-identical blood and analyzed with regard to clotting time, signs of inflammation and cell infiltration. Composite islet-HAEC graft survival was assessed after transplantation to athymic (nu/nu) nude mice. Exposed to blood, HAEC-coated islets induced less activation of coagulation and complement compared to control islets. Also, platelet and leukocyte consumption in blood was decreased. Clots with entrapped HAEC-coated islets showed less infiltration of CD11b+ cells. The extent of protection correlated to the level of HAEC coverage. Transplanted composite grafts stained positive for insulin and PECAM-1 demonstrating presence of both islets and HAEC within the islet graft 7 weeks after transplantation. Composite islet-HAEC grafts reduce all components of IBMIR. Refinement of the technique will allow introduction of composite islet-EC grafts in clinical islet transplantation, using autologous EC expanded in vitro and kept frozen until allogeneic islets become available for that specific recipient.