Interferon-gamma (IFN-gamma) is a pleiotropic cytokine involved in antiproliferative and anti-virus responses, immune surveillance and tumor suppression. These biological responses to IFN-gamma are mainly mediated by the regulation of gene expression. It has been reported that growth-inhibitory role of IFN-gamma is dependent on activation of signal transducers and activators of transcription 1 (STAT1); however, the molecular basis downstream of STAT1 remains unclear. Here, we report that an IFN-gamma-induced gene, interferon-induced transmembrane protein 1 (IFITM1), plays a key role in the antiproliferative action of IFN-gamma. Overexpression of IFITM1 negatively regulated cell growth, whereas suppression of IFITM1 blocked the antiproliferative effect of IFN-gamma, accelerated the cell growth rate and conferred tumorigenicity to a non-malignant hepatocyte in nude mice. Further, IFITM1 could inhibit the activity of extracellular signal-regulated kinase, enhance the transcriptional activity of p53 and stabilize the p53 protein by inhibiting p53 phosphorylation on Thr55. Suppression of p53 reduced the growth-inhibitory capacity of both IFITM1 and IFN-gamma. Therefore, these findings indicated that the antiproliferative action of IFN-gamma requires the induction of IFITM1, and provided a crosstalk between two well-known signaling mediators, STAT1 and p53, both of which play critical roles in tumor suppression.