Hepatitis C virus (HCV) is one of the endemic viral infections in Egypt and there is no vaccine for HCV, and the only available treatment, a combination of α-interferon and ribavirin, is effective in a minority of patients, various viral and host factors may affect response to treatment. The aim of this work is to examine changes in lymphocyte subpopulations in the peripheral blood of chronic hepatitis C patients before and after interferon therapy and to compare between immunological and virologic predictors of treatment outcome. Patients and Methods: Immunophenotyping of peripheral blood lymphocyte subpopulations of twenty chronic HCV patients were studied by four-color flowcytometry before and 3 hours after the first interferon injection, and at 4 and 12 weeks during therapy. The percentages of total T, T helper, activated T helper, T regulatory, T cytotoxic, activated T cytotoxic, T memory, natural killer and B lymphocytes were evaluated with the use of CD3, CD4, CD8,CD25, CD127, HLA-DR, CD45RO, CD56 and CD19 conjugated monoclonal antibodies respectively. Results: No significant difference was found in the ratio of different lymphocyte subpopulations in patients before and 3 hours after administration of interferon; after 4 weeks and after 12 weeks of treatment, except for CD3CD8 cytotoxic T lymphocytes which showed significant difference between complete responders and non responders (significant decrease in cytotoxic cell ratio after 3 hours as compared to pretreatment). Conclusions: Although measurement of HCV RNA viral load is the gold standard for assessment of response to therapy, immunophenotyping of cytotoxic T lymphocytes can be used as an immunological predictor of outcome of treatment. This immunological predictor of outcome of treatment (Cytotoxic T lymphocyte decrease at 3 hours) is earlier than the virologic predictor (HCV RNA at 12 and 24 weeks), and can thus decrease the risk of prolonged futile interferon therapy, also measurement of HCV RNA viral load at 12 weeks is not sufficient and should repeated at 24 weeks of treatment.