Studies of interferon-alpha (IFN-alpha) therapy for chronic hepatitis C have focused on viral clearance; however, few have evaluated patient's health-related quality of life during therapy. This study evaluates health-related quality of life and the prevalence of anxiety and depression in patients with chronic hepatitis C before, during, and following IFN-alpha therapy. Patients undergoing IFN-alpha therapy for chronic hepatitis C were asked to complete health status measures as well as anxiety and depression inventories before, during, and following IFN-alpha therapy. These measures were compared to the results of healthy adults in the general US population. Thirty-eight of forty-eight eligible patients (79%) with chronic hepatitis C completed the questionnaires. Respondents demonstrated a significant increase in depression during the sixth month of interferon therapy in comparison to pretreatment results. Anxiety scores improved significantly after one month of IFN-alpha in comparison to pretreatment results. Scores on the health status measures did not vary with IFN-alpha therapy. Patient responses were analyzed with respect to biochemical response (normalized transaminases) to IFN-alpha. IFN-alpha responders, who were aware of their transaminase results, exhibited lower scores on anxiety subscales during and after therapy (P = 0.02-0.04). Scores on the health status subscale, role emotional, improved in IFN-alpha responders compared to nonresponders during the sixth month of therapy (P = 0.02). Response to IFN-alpha therapy was not associated with any other differences on subscale analysis. Patients with chronic hepatitis C exhibited health perceptions similar to the general US population, and these were unchanged during IFN-alpha therapy. However, the incidence of depression significantly increased during the sixth month of IFN-alpha therapy. IFN-alpha responders exhibited fewer emotional problems as well as a lower incidence of anxiety during and following therapy.