Despite advances in clinical islet transplantation, intraportal islet delivery is limited by engraftment, neovascularization, immune protection and functional survival. An alternative pre-vascularized, subcutaneous device could solve these issues and be relevant for future transplantation of insulin-producing stem cells. We herein report a first-in-human trial with a newly developed pre-vascularized subcutaneously placed pouch as an innovative approach for human islet implantation. Three longstanding type 1 diabetes subjects underwent subcutaneous implantation of therapeutic and sentinel pouches. After a median delay of 53 days (range 22-130), inner rods were removed and voids filled with purified human islets. In this preliminary experience, the primary endpoint of safety was met, and surviving, vascularized human islets were visualized on histological examination after pouch explantation by 6 weeks post-transplant. Islets retained macro-structure of beta and alpha cells in all cases, and demonstrated neovascularization. The secondary endpoint of insulin independence efficacy was not met, despite transplantation of a substantial islet mass in each case. Early peak C-peptide at 24 hours followed by absence subsequently suggested early functional engraftment failure in all cases.