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Hepatitis C virus (HCV)-associated antigens, such as the core and nonstructural antigens, activate host innate immune systems via Toll-like receptors (TLRs). We previously showed that chronic exposure to the core antigen induces hyporesponsiveness to TLR ligands in antigen-presenting cells via activation of TLR2 and that stimulation with TLR ligands results in impaired IL-6 production by peripheral blood monocytes from HCV-infected patients. In the present study, peripheral blood mononuclear cells (PBMCs) isolated from patients with chronic HCV or hepatitis B virus (HBV) infection were stimulated with TLR ligands to determine the production of IL-6 and IL-8 and to identify the clinical parameters associated with hyporesponsiveness to TLR ligands in patients with chronic HCV infection. The results showed that pro-inflammatory cytokine responses to TLR ligands were suppressed in PBMCs isolated from HCV-infected, but not HBV-infected, patients. The reduced cytokine responses to TLR ligands seen in HCV-infected patients correlated with platelet counts and serum prothrombin time levels. In contrast, there was no correlation between TLR-induced cytokine responses and serum levels of core antigen. Thus, hyporesponsiveness to TLR ligands in HCV-infected patients is correlated with liver dysfunction. In conclusion, both host factors and viral factors may be involved in the generation of hyporesponsiveness to TLR ligands in patients with chronic HCV infection.