Peripheral blood mononuclear cells (PBMCs) play a critical role in clearing hepatitis C virus (HCV). PBMC defects have been linked with HCV infection; however, the underlying mechanisms remain obscure. We hypothesized that PBMCs of HCV-infected patients are more susceptible to programmed cell death (PCD), and are therefore unable to clear HCV. We compared spontaneous PBMC PCD and cytokine [interleukin (IL)-1, -6, -8, -10, and -12] secretion between untreated (naive) HCV+ and treated [sustained responder (SR)] patients with HCV, and HCV-healthy controls. Spontaneous PBMC PCD was assessed by annexin-V fluorescein isothiocyanate/propidiumiodide staining, and cytokine levels were measured by cytometric bead array. Differences between groups were analyzed through paired and nonpaired t tests and Mann-Whitney U test. The rate of spontaneous PCD was higher in PBMCs of naive HCV+ patients (p < 0.0001) and SR-HCV patients (p < 0.002) than in HCV-controls. Significantly low levels of IL-8, -6, and -10 were detected in the supernatant of cell cultures of PBMCs from naive HCV+ (p < 0.05) and SR-HCV (p < 0.05) patients relative to HCV-controls. There was no difference between the naive HCV+ and SR-HCV groups in terms of PBMC PCD rate or cytokine levels. The present findings indicate that HCV infection is associated with increased PBMC susceptibility to PCD and decreased production of IL-8, -6, and -10.