Immunomodulatory properties have been recognized for human alpha-1 antitrypsin (hAAT). However, production of anti-hAAT antibodies in mice may inactivate the protein. In this study, we evaluated the effects of chronic hAAT administration on allogeneic islet graft survival. Chemically diabetic mice lacking an efficient humoral response due to the targeted disruption of the Ig mu-chain (muMT mice) or wild-type (WT) C57BL/6 mice received DBA/2 mouse islets under the kidney capsule. hAAT (Prolastin or Aralast) was given intraperitoneally on day 0 and every 3 days thereafter. Control animals received no treatment. hAAT administration in WT mice resulted in prolongation of islet allograft survival in a dose-dependent fashion in both hAAT-treated groups. Lack of Ig response (muMT mice) per se conferred a beneficial effect on graft survival that worsened in the Prolastin-treated groups but improved in the Aralast-treated group. Our data indicate that systemic administration of hAAT results in prolongation of islet allograft survival. Absence of mature B cells and Ig mu-chain resulted in improved graft survival, pointing to a role for B cells in the rejection process in this model. Treatment with Prolastin worsened graft survival in muMT mice, whereas Aralast did improve it, suggesting a different efficacy and possible actions of the two drug formulations.