Our purpose was to determine in HCV-infected patients whether T-lymphocyte sub-populations were modified before and during interferon-alpha and ribavirin treatment, and whether this correlated with virological response. Twenty-two naive patients were given IFN-alpha 3 Million Units three times per week for 24 or 48 weeks and ribavirin. Sustained virological response corresponded to undetectable serum HCV RNA at treatment completion and 6 months later. Total blood lymphocyte counts and CD3(+)CD4(+), CD3(+)CD8(+), CD3(+)CD4(+)HLA-DR(+), and CD3(+)CD8(+)HLA-DR(+) lymphocyte subsets evaluated before, during, and after treatment were compared to values from 37 healthy subjects. At inclusion, patients and controls had similar total lymphocyte counts. CD3(+)CD4(+) counts and percentages were significantly higher in HCV patients. HLA-DR expression was also increased in CD4(+) (p < 0.0001) and CD8(+) T-cells (p = 0.0008) as compared with controls. During treatment, all lymphocyte subset counts and percentage decreased except the CD3(+)CD4(+) T-cell percentage which increased. Moreover, after 1 month of treatment, virological responders exhibited higher CD4(+) counts than nonresponders (p = 0.025), whereas they did not differ at inclusion or during the 2nd to 6th months of treatment. After treatment completion, all populations returned to baseline values. These results suggest that CD3(+)CD4(+) T-lymphocyte percentage increase under treatment could be related to IFN immunomodulation and associated with virological response.