The transcription factor c-Myc has been previously shown to be phosphorylated and stabilized by NEMO through direct interaction in the nucleus. Here, we show that NEMO induces up-regulation of the c-Myc target protein, γ-glutamyl-cysteine synthetase (γ-GCS), leading to an increase of intracellular glutathione (GSH) levels and simultaneous enhancement of redox-controlling capacity. NEMO enhanced c-Myc recruitment to γ-GCS promoters and c-Myc was essential for NEMO-mediated γ-GCS up-regulation. The phosphorylation and stabilization of c-Myc by NEMO rendered cells more resistant to ionizing radiation (IR). Thus, the interaction between NEMO and c-Myc may be targeted for the development of strategies to overcome the resistance to radiotherapy.