X-linked severe combined immunodeficiency (SCID-X1), caused by a defect of the cytokine receptor common gamma chain (γc), has been successfully treated by gene therapy in the clinic. However, the occurrence of leukemia in several patients preceded by loss of oligoclonality revealed that treatment is associated with a risk inherent to the genetic modification of hematopoietic stem cells. In this study, we developed a safety approach that allows the specific elimination of gene-modified cells. For this, a small peptide sequence (myc-tag) was introduced into the murine γc protein. Cells expressing the modified chain can be detected with a myc-specific antibody by flow cytometry and are effectively depleted in vitro in the presence of complement factors. Further, thymic-derived T cells from mice reconstituted with myc-tagged γc-transduced bone marrow stem cells can be depleted by antibody administration in vivo. Similarly, specific complement-mediated lysis was observed for human T cells expressing the human myc-tagged γc. In a cell proliferation assay, the modified cytokine receptor chain showed no functional impairment compared to the wild-type chain. In sum, we show proof-of-principle of a safety mechanism for SCID-X1 gene therapy that would allow elimination of gene-corrected cells in a patient upon observation of monoclonal outgrowth.