Multiple interferon-stimulated genes (ISGs) involving T-cell activation are upregulated during initial interferon-alpha-based therapy for chronic hepatitis C virus (HCV) infection. However, the long-term impact on therapeutic outcome in patients remains unknown. In this study, the effects of anti-HCV therapy on the surface expression of HLA-ABC, CD86, and CD28 were longitudinally assessed. These proteins are integral membrane receptors of antigen presentation and triggering of costimulatory signals for activating CD8+ T cells. Peripheral blood mononuclear cells were collected at baseline and post-treatment for 1 day, and 2, 4, 12, and 24 weeks, respectively. This treatment led to a time-related elevation of membrane levels of HLA-ABC and CD86 on B-cells and monocytes in patients with a sustained response (n = 23), but not in those without (n = 8). Meanwhile, upregulation of CD28 on CD4+ and CD8+ T cells was comparable in both groups of sustained responders and non-responders. Steady increases in the B cells' surface and intracellular HLA-ABC were observed, thus, the surface-to-intracellular ratios did not alter over the period of treatment. Furthermore, multivariate analysis shows that increased HLA-ABC on monocytes by week 12 correlates significantly with sustained response (P = 0.033). In conclusion, differential modulation of T-cell activation ISGs, such as HLA-ABC and CD86 might correlate with the outcome of interferon-alpha-based therapy in chronic hepatitis C patients.