Several approaches to target insulin-like growth factor-1 (IGF-1) signaling have resulted in the inhibition of the growth of a broad range of tumor cells. Malignant T cells are insensitive to the antiproliferative effects of the interferon-gamma (IFN-gamma)/signal transducer and activator of transcription 1 (STAT1) pathway because of the IGF-1-dependent internalization of the IFN-gammaR2 signaling chain. Here we show that human malignant T cells are also resistant to the growth inhibitory effect of both the IGF-1 receptor-specific inhibitor picropodophyllin (PPP) and retrovirus-mediated gene transfer of a dominant negative IGF-1 receptor. However, blockade of IGF-1 receptor perturbs IFN-gammaR2 internalization and induces its cell surface accumulation in malignant T cells. This allows the reinstatement of the IFN-gamma-induced STAT1 activation, a high expression of proapoptotic molecules, and the suppression of malignant T-cell growth both in vitro and in vivo in a severe combined immunodeficiency (SCID) mouse model. These data indicate that the inhibition of IGF-1 signaling combined with IFN-gamma administration could be a promising approach to suppress the growth of neoplastic T cells resistant to each treatment on its own.