Mutations in the gene encoding the common cytokine receptor gamma chain (γ_c) are responsible for human X-linked severe combined immunodeficiency disease (SCIDX1). We have used a γ_c-deficient mouse model to test the feasibility and potential toxicity of γ_c gene transfer as a therapy for SCIDX1. A retrovirus harboring the murine γ_c chain was introduced into γ_c-deficient bone marrow cells, which were then transplanted into alymphoid RAG2/γ_cdouble-deficient recipient mice. Circulating lymphocytes appeared 4 weeks postgraft and achieved steady-state levels by 8 weeks. The mature lymphocytes present in the grafted mice had integrated the γ_c transgene, expressed γ_c transcripts, and were able to proliferate in response to γ_c-dependent cytokines. The γ_c-transduced animals demonstrated (1) normal levels of immunoglobulin subclasses, including immunoglobulin G1 (IgG1) and IgG2a (which are severely decreased in γ_c^- mice); (2) the ability to mount an antigen-specific, T-dependent antibody response showing effective in vivo T-B cell cooperation, and (3) the presence of gut-associated cryptopatches and intraepithelial lymphocytes. Importantly, peripheral B and T cells were still present 47 weeks after a primary graft, and animals receiving a secondary graft of γ_c-transduced bone marrow cells demonstrated peripheral lymphoid reconstitution. That γ_c gene transfer to hematopoietic precursor cells can correct the immune system abnormalities in γ_c^- mice supports the feasibility of in vivo retroviral gene transfer as a treatment for human SCIDX1.