Sex has been reported to influence the rates of viral clearance in hepatitis C virus (HCV)-infected patients. However, little is known regarding the influence of sex on the host genetic response to HCV, which is mediated by the expression of interferon (IFN)-stimulated genes (ISGs) after the activation of janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by IFN. Thus, we investigated gender differences in MxA genetic profile, which is a downstream reliable marker for JAK/STAT pathway activation. In all, 40 untreated HCV-infected patients were subclassified into premenopausal, postmenopausal, and male patients. The peripheral blood mononuclear cells (PBMCs) from premenopausal women showed the highest MxA gene expression compared to both postmenopausal females and males before and after IFN stimulation. The prestimulation of PBMCs with 17beta-estradiol prior to IFN treatment resulted in a decrease of MxA expression in all groups of patients. That was confirmed by the reversal of this effect using estrogen antagonist ICI182/780. This study demonstrates for the first time the presence of gender variations in the genetic response to chronic HCV infection and to interferon treatment. It also clarifies that estrogen is not the key player in enhancing the JAK/STAT pathway.