Objective(s): The objectives of present study were to investigate the response of chronic hepatitis C (CHC) patients to pegylated interferon alpha plus ribavirin (PEG-INF/RBV) combination therapy, to identify factors that could predict their response to treatment and to assess their health-related quality of life (HRQOL) before, during and after PEG-INF/RBV combination therapy. Methods: An intervention study (one group pre-test - post-test design) was used. Data were collected from 300 CHC patients who attended the Hepatology and Interferon Therapy Unit at Gamal Abd El Naser Insurance Hospital using a pre-designed structured interviewing questionnaire and viral hepatitis C quality of life questionnaire. Review of the patients' medical records and their laboratory investigations was also carried out. Results: The cumulative seronegativity rate of treated patients was 74%. The proportion of CHC patients who survived seronegativity was 0.270 at the 12^th week, 0.261 at the 24^th week and 0.250 at the 48^th week of treatment. Patients' age and viral load significantly affected seronegativity. Significant univariate main effects for age were statistically associated with poor HRQOL in the domains of physical functioning, role limitations due to physical health, emotional problems and pain. Presence of chronic diseases and HC viral load had a significant effect on physical functioning, role limitations due to physical health problems, emotional problems and pain. All domains of the HRQOL short form (SF36) decreased by the end of the 4^th week and started to increase at the 24^th and 48^th weeks of the follow up period. Conclusion: The proportion of CHC patients who survived seronegativity was 0.250 at the 48^th week of treatment.  Factors associated with seroconversion were age and hepatitis C virus (HCV) load. CHC patients aged 55 years and above, those with chronic diseases and those with HC viral load of ≥ 900,000 IU/ml were found to be statistically associated with poor HRQOL. All the domains of the SF36 decreased by the end of the 4^th week and started to increase at the 24^th and 48^th weeks of follow up period.