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Hepatitis C virus (HCV) is a major health concern in Egypt being highly prevalent among Egyptians. The two genders experience different responses to HCV infection and show variations in response to interferon (IFN)-based therapy that may be attributed to sex hormones. We previously demonstrated the suppressive effect of 17β-estradiol (E2) on the expression of the IFN-stimulated gene MxA in HCV-infected peripheral blood mononuclear cells (PBMCs). The selective oestrogen receptor (ER) modulator Tamoxifen has been shown to have an antiviral effect against HCV, but its effect on the host immune response is unknown. We investigated the effect of Tamoxifen on the IFN signalling pathways in PBMCs of HCV-infected Egyptian females. We pooled PBMCs and treated then with exogenous interferon alpha (IFNα) or the TLR7 ligand, Imiquimod, and quantified the relative expressions of MxA using RTqPCR. Studies were performed with and without Tamoxifen pretreatment. Pretreatment with Tamoxifen reversed the suppressive effect of E2 on the JAK-STAT pathway in IFNα-treated PBMCs as indicated by a significant increase in MxA expression (P = 0.05*). Tamoxifen pretreatment also significantly upregulated MxA expression in Imiquimod-treated PBMCs (P = 0.0011**), an effect not ascribed to ER blocking nor to an upregulation in TLR7 expression because Tamoxifen showed no potentiating effect on the expression of the receptor. In conclusion, our findings reveal that Tamoxifen has immunomodulatory effects whereby it enhances the host IFN signalling pathways during HCV infection.