The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet β-cell mass, our center measured β-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet β-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in β-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets.