The refractoriness of T cells to the interferon-γ (IFN-γ)/signal transducer and activator of transcription 1 (STAT1) pathway, which shields them from the antiproliferative effect of IFN-γ, is attributed mainly to down-regulation of the IFN-γR2 signaling chain. However, the mechanisms responsible for this down-regulation are unclear. Here we show that iron uptake mediated by the transferrin receptor (TfR) delivers a signal that leads to IFN-γR2 internalization and thus plays an essential role in attenuating activation of the IFN-γ/STAT1 pathway in human T lymphocytes. The effect of iron on IFN-γR2 internalization was specific as it did not affect expression of the IFN-γR1 binding chain. Deferoxamine (DFO), an iron-chelating agent, up-regulated IFN-γR2 surface expression and reinstated IFN-γ/STAT1 activation in proliferating T lymphocytes. Resistance of malignant T cells to the antiproliferative effect of IFN-γ in vitro was abrogated by addition of DFO. Conversely, iron inhibited IFN-γ–induced apoptosis in malignant T cells in serum-free conditions. In combination but not individually, DFO and IFN-γ strongly inhibited growth of human malignant T cells in an in vivo severe combined immunodeficient (SCID) mouse model. These data provide valuable insights for novel therapeutic approaches aimed at reinstating the IFN-γ/STAT1 apoptotic signaling pathway in autoreactive or neoplastic T cells by means of iron chelation.