Although evidence of virologic elimination, normalization of serum alanine aminotransferase levels, and reduction in liver inflammation are the principal therapeutic outcome goals in chronic hepatitis C patients, improvement in health-related quality of life (HQL) is also an important aspect of therapeutic outcome. In a recent report of chronic hepatitis C patients treated for 24 weeks with interferon, sustained virologic response (24 weeks post-treatment) was associated with improvement in HQL compared with nonresponse. We report on the relationship between sustained virologic response and Hepatitis Quality-of-Life Questionnaire (HQLQ) survey results of patients who relapsed after a previous course of interferon alfa who were subsequently treated with recombinant interferon alfa-2b (rIFN-alpha 2b) either alone or in combination with ribavirin. The HQLQ was administered at baseline, at treatment Weeks 12 and 24, and at follow-up Weeks 12 and 24. All patients received rIFN-alpha 2b 3 million International Units by subcutaneous injection three times weekly plus either oral ribavirin (1,000 or 1,200 mg) or placebo daily for 24 weeks. At baseline, patients scored lower than adjusted population norms in HQL. Relative to patients treated with rIFN-alpha 2b monotherapy, patients receiving combination therapy showed better HQL in 6 of 13 domains. Furthermore, sustained virologic response in either treatment group was associated with improvement in the scores of both generic and hepatitis-specific HQL survey domains. These results indicate that successful therapeutic resolution of hepatitis C infection improves HQL as assessed by generic and hepatitis C-specific measures of functional health and well-being. Furthermore, improvements in HQL outcome measures may predict reduced demand for health care resources and greater productivity in the workplace.