Hepatitis C infects nearly 4 million Americans. Most have chronic hepatitis C (CHC), which progresses to cirrhosis in about 20% of patients. Interferon treatment leads to transient responses in about 40% of patients and apparent eradication of infection in 7% to 40% of patients. In this report, we document the impact of CHC on health-related quality of life (HQL), and changes in HQL among treatment responders. Three hundred twenty-four CHC patients from 10 countries who had relapsed after responding to interferon-alfa therapy were randomized to monotherapy (IFN alfa-2b + placebo) or combination therapy (IFN alfa-2b + ribavirin), treated for 24 weeks, and followed up for 24 weeks. HQL was assessed using the Hepatitis Quality of Life Questionnaire (HQLQ), containing the generic SF-36 Health Survey, three additional generic scales, and two hepatitis-specific scales. Before treatment, CHC patients were impaired in 5 of 8 SF-36 concepts (physical functioning, role-physical, general health, vitality, and social functioning) in comparison with matched population norms. Sustained virological response (SVR) to treatment yielded improvements on three generic scales (vitality, social functioning, and health distress) and the CHC-specific health distress scale. Overall response to treatment (SVR plus histological improvement) yielded the same pattern of improvements with additional gains in generic general health and CHC-specific limitations. Successful treatment of CHC improved HQL as measured by both CHC-specific and generic measures of functional health and well being.