IFN-gamma is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-gamma receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-gamma by repressing transcription of IFN-gamma-induced genes. Thus far, few studies have explored the influences of IFN-gamma on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-gamma in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-gamma was increased in tumor tissues and positively correlated with tumor progression and IRF-2 expression, whereas the level of IFNGR1 was decreased and negatively correlated with tumor progression and IRF-2 expression. Consistently, in vitro experiments showed that low concentration of IFN-gamma induced the expression of IRF-2 with potential promotion of cell growth, and moreover, IRF-2 was able to suppress IFNGR1 transcription in human esophageal cancer cells by binding a specific motif in IFNGR1 promoter, which lowered the sensitivity of esophageal cancer cells to IFN-gamma. Taken together, our results disclosed a new IRF-2-mediated inhibitory mechanism for IFN-gamma-induced pathway in esophageal cancer cells: IFN-gamma induced IRF-2 up-regulation, then up-regulated IRF-2 decreased endogenous IFNGR1 level, and finally, the loss of IFNGR1 turned to enhance the resistance of esophageal cancer cells to IFN-gamma. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-gamma and IFNGR1 in human esophageal cancers.