The optimal preparation for stem cell transplantation (SCT) in children with congenital immunodeficiencies is currently unknown. In all, 81 children with immunodeficiency underwent 82 SCTs using reduced-intensity conditioning (RIC). The incidence of significant GVHD was low; viral reactivation was prominent with an unexpected increase in EBV reactivation; immune reconstitution was similar between different donor groups and comparable to conventional SCT. Overall, 68/81 (84%) survive with no significant difference between donor types or between severe combined immunodeficiency (SCID) and non-SCID diseases. Findings suggest a significant survival advantage in the unrelated donor setting for RIC compared to conventional SCT.