Mutations in the ZAP-70 protein tyrosine kinase gene result in a severe combined immunodeficiency (SCID) characterized by a selective inability to produce CD8⁺ T cells and a signal transduction defect in peripheral CD4⁺ cells. Transplantation of genetically modified hematopoietic progenitor cells that express the wild-type ZAP-70 gene may provide significant benefit to some of these infants. The feasibility of stem cell gene correction for human ZAP-70 deficiency was assessed using a ZAP-70 knock-out model. ZAP-70–deficient murine bone marrow progenitor cells were transduced with a retroviral vector expressing the human ZAP-70 gene. Engraftment of these cells in irradiated ZAP-70–deficient animals resulted in the development of mature CD4⁺ and CD8⁺ T cells. In marked contrast, both populations were absent in ZAP-70^−/− mice undergoing transplantation with bone marrow progenitor cells transduced with a control vector. Importantly, ZAP-70–reconstituted T cells proliferated in response to T-cell receptor stimulation. Moreover, these ZAP-70–expressing T cells demonstrated a diverse T-cell receptor repertoire as monitored by the relative usage of each T-cell receptor β chain hypervariable region subfamily. The presence of ZAP-70 in B cells did not affect either lipopolysaccharide- or lipopolysaccharide/interleukin-4–mediated immunoglobulin isotype switching. Altogether, these data indicate that retroviral-mediated gene transfer of the ZAP-70 gene may prove to have a therapeutic benefit for patients with ZAP-70–SCID.