The liver is the preferred site for clinical islet transplantation (ITx) but is not ideal due to several limitations affecting engraftment. We evaluated the safety and efficacy of ITx in the omentum within a resorbable biologic scaffold in a 43-year-old woman with 25-year history of type 1 diabetes complicated by hypoglycemia unawareness and severe hypoglycemia. Pre-transplant insulin requirements were 31 units/day, HbA1c 6.8%, weight 53.4 Kg, and BMI 21.5 Kg/m2. 602,395 islet equivalents from a single donor were combined with autologous plasma and layered laparoscopically on the omentum. Recombinant thrombin (Recothrom®) was added followed by an additional autologous plasma layer to generate a scaffold adherent to the omental surface. The omentum was folded over the scaffold and additional thrombin used to seal the edges. Induction immunosuppression consisted of anti-thymocyte globulin (Thymoglobulin®) and etanercept (Enbrel®). Tacrolimus and mycophenolate sodium were used for maintenance. There were no surgical complications. Insulin independence was attained on day 17 post-ITx. At day 75, fasting and 90min C-peptide post mixed meal tolerance test were 0.80 and 2.79 ng/mL with corresponding glucose of 107 and 175 mg/dL, respectively. At one year, fasting C-peptide declined to 0.43 ng/mL and 90min C-peptide to 1.22 ng/mL. Fasting glucose was 120 mg/dL and 90min glucose 266 mg/dL with HbA1c of 6.0%. At 15 months, insulin degludec (4 units daily) was introduced resulting in stabilization of glucose control. Patient maintains excellent glycemic control at 16 months with 7-day mean capillary blood glucose 100±14 mg/dL (n=28) on 4 units of basal insulin and without hypoglycemia. An islet-containing biologic scaffold transplanted within an omental fold appears to be a safe alternative to intra-hepatic ITx with persistent graft function observed over 15 months. Long-term follow up is required to determine sustainability of graft function with this novel strategy and implantation site.