Health-related quality of life (HRQoL) during therapy was found to be improved in patients treated with peginterferon alpha-2a compared to patients receiving interferon alpha-2a. This study aimed to assess the effect of different pegylated interferon therapies used in the treatment of patients with chronic hepatitis C on HRQoL. Forty chronic hepatitis C patients were enrolled. 22 patients were given a combination of peginterferon alpha-2a plus ribavirin and 18 patients received a combination of peginterferon alpha-2b plus ribavirin for 48 weeks. Patients completed a Short Form-36 (SF-36) questionnaire at the start of treatment and at week 12, week 24 and week 48 of treatment and week 24 posttreatment to evaluate HRQoL. In conclusion, the effect of both combination treatments on quality of life was similar.