Myeloablative conditioning regimens may cause significant life threatening transplant related toxicities in patients with immunodeficiency disorders, particularly in patients with co-morbid conditions. This current study was designed to determine whether an immunosuppressive nonmyeloablative regimen would safely enable stable donor engraftment of hematopoietic cells in patients with immunodeficiency disorders who were ineligible for myeloablative conditioning regimens because of life-threatening infections or organ dysfunction. Fourteen patients with severe combined immunodeficiency disorder (SCID; n=3), common variable immunodeficiency (CVID; n=1), T-cell immunodeficiency disorder (TCD; n=3), Wiskott-Aldrich syndrome (WAS; n=2), CD40 Ligand deficiency (CD40LD; n=2), immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX; n=1), X-linked agammaglobulinemia (XLA; n=1) and chronic granulomatous disease (CGD; n=1) received HLA-matched related (n=7) or unrelated (n=7) hematopoietic cell grafts from marrow (n = 8), peripheral blood stem cell (n = 5), or umbilical cord blood (n = 1). All patients were given postgrafting immunosuppression with MMF and CSP. Two patients had no pre-transplant conditioning, whereas host immunosuppression was provided by 200 cGy TBI alone (n=3) or in combination with 90 mg/m2 fludarabine (n=9) before hematopoietic cell transplantation (HCT). Mixed (n=5) or full (n=5) donor cell chimerism was established in 10 patients. Four patients required second HCT (n=3) or donor lymphocyte infusion (n=1) due to either T cell graft rejection (n=1), loss of the granulocyte graft (n=1), or low levels of T cell chimerism (n=2). Mortality by days 100 and 180 was 0%. The cumulative incidences of grade II–IV and III–IV acute graft versus host disease (GVHD) were 79% and 14%, respectively. The 1-year incidence of extensive chronic GHVD was 64%. Median follow up for the living recipients was 3 (range, 0.8–6.4) years. The 2 year overall survival, event free survival and transplant related mortality were 68%, 60%, and 16%, respectively. In 7 of the 10 patients with stable donor engraftment correction of immune dysfunction was documented. Specifically, the 4 patients with SCID (n=3) and CVID (n=1) had normal T cell numbers and function following HCT. One patient with WAS had correction of T cell function and platelet numbers after HCT; however subsequently died of B cell non-EBV lymphoma. In addition, 1 patient with CD40LD showed increases in functional CD40 ligand expressing T-cells and response to a neoantigen. Finally, 1 patient with CGD exhibited a normal neutrophil oxidative burst following HCT. Three patients (TCD n=2, CD40LD n=1) were not evaluable for disease response due to continued immunosuppression for chronic GVHD. These results indicate that postgrafting immunosuppression plus nonmyeloablative HCT markedly reduces early HCT related mortality among high-risk patients with immunodeficiency disorders.