X-linked severe combined immunodeficiency (XSCID) is a life-threatening syndrome in which both cellular and humoral immunity are profoundly compromised. This disease results from mutations in the IL2RG gene, which encodes the common cytokine receptor gamma chain, gamma(c). Previously, we generated gamma(c)-deficient mice as a murine model of XSCID. We have now used lethally irradiated gamma(c)-deficient mice to evaluate a gene therapeutic approach for treatment of this disease. Transfer of the human gamma(c) gene to repopulating hematopoietic stem cells using an ecotropic retrovirus resulted in an increase in T cells, B cells, natural killer (NK) cells, and intestinal intraepithelial lymphocytes, as well as normalization of the CD4:CD8 T-cell ratio and of serum Ig levels. In addition, the restored cells could proliferate in response to interleukin-2 (IL-2). Thus, our results provide added support that gene therapy is a feasible therapeutic strategy for XSCID. Moreover, because we used a vector directing expression of human gamma(c) to correct a defect in gamma(c)-deficient mice, these data also indicate that human gamma(c) can cooperate with the distinctive cytokine receptor chains such as IL-2Rbeta and IL-7Ralpha to mediate responses to murine cytokines in vivo.