It is still controversial whether alterations in helper-T cell subpopulations contribute to the pathogenesis and clinical characteristics of chronic hepatitis C. The aim of this study was to clarify this issue, particularly in relation to interferon therapy. Thirty-one patients with histologically proven chronic hepatitis C were treated by conventional interferon (IFN) monotherapy for 6 months, and virological responses were evaluated by polymerase chain reaction 6 months later. Helper-T cell subpopulations, Th-1 and Th-2, were determined in peripheral blood by intracellular cytokine assay using flow cytometry. In chronic hepatitis C, the percentage of Th-1 and Th-2 subpopulations in peripheral blood were significantly increased, by 1.4-fold as compared with normal controls. Serum levels of ALT were inversely proportional to the percentage of Th-1 subpopulations, while directly proportional to that of Th-2 subpopulations. In nonresponders (N = 16) to interferon therapy, the percentage of Th-1 subpopulations and Th-1/Th-2 ratio were significantly higher than those in complete responders (N = 15). By multivariate logistic regression analysis, HCV genotype non-lb, HCV viral load less than 500 kilocopies/ml, and the lower Th-1/Th-2 ratio could independently merit favorable long-term virological responses. Helper-T cell subpopulations, Th-1 and Th-2, seem to contribute to progression of chronic hepatitis C in a reciprocal fashion. The imbalance between the two subpopulations may determine the final outcome of interferon therapy as one of the host factors.