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The discovery of direct‐acting antivirals (DAAs) has revolutionized the treatment of hepatitis C worldwide. In contrast, pegylated interferon‐alpha (PEG IFN‐α), the older regimen, had limited success. However, the effect of DAAs on the expression of immunomodulatory genes involved in liver pathologies remains ambiguous. The objective of this study was to explore and contrast the effects of DAAs and PEG IFN‐α on the expression of selected immunomodulatory genes. Fifty individuals were enrolled in the study and they were divided into five categories; healthy individuals, treatment‐naive, DAAs‐responders, DAAs‐nonresponders, and interferon‐relapsers. The effect of the therapies on the expression of transforming growth factor‐beta (TGF‐β), tumor necrosis factor‐alpha (TNF‐α), suppressor of cytokine signaling 3 (SOCS‐3), copper/zinc superoxide dismutase (Cu/Zn SOD), interleukin 10 (IL‐10), and collagen …