Antiviral treatment for chronic hepatitis C infections is currently judged as being successful if, at least six months after therapy, blood tests for hepatitis C viral RNA are negative; this has been called a sustained viral response. In the past, other outcomes for treatment have included improvements in biochemical tests (especially liver enzyme tests such as the serum alanine aminotransferase) or evidence of reduced inflammation and/or fibrosis on subsequent liver biopsies. All of these outcomes are tests, and it has been assumed that if the test gets better the patient will as well. However, there is no direct evidence that has proven that these outcomes are valid because there have been no long-term trials that have shown that an improvement in these tests translates into reduced mortality or morbidity. Patients who fail to have sustained viral responses after an initial course of therapy do become potential candidates for retreatment; some of them may be intolerant to ribavirin, and possibly even the newer protease inhibitors, so retreatment would have to be with interferon alone. It has also been speculated that long-term treatment (namely treatment for several years) might be beneficial; such long-term therapy would be further complicated if multiple drugs were used because of the additional drug toxicities and costs, so interferon alone could be considered. This review addressed the ability of interferon monotherapy to favorably alter the clinical course of chronic hepatitis C when it is used to retreat patients who failed at least one previous course of therapy. Seven trials were identified, including two large ones (a total of 1676 patients), known as "HALT-C" and "EPIC3", that specifically were designed to use low-dose pegylated interferon for three to five years in patients with evidence on liver biopsy of severe fibrosis and who had failed to have a sustained viral response to a course of standard combination (pegylated interferon plus ribavirin) therapy in the past. Both trials were at low risk of bias. A third trial designed to address the use of pegylated interferon monotherapy for 48 weeks in improving survival in patients with cirrhosis (Childs A or B) was terminated early because of the results of the HALT-C and EPIC3 trials, so three trials have provided mortality and hepatic morbidity data. When all three trials were considered, there was no significant effect of the treatment on either all-cause mortality (78/843 (9.3%) versus 62/867 (7.2%); risk ratio (RR) 1.30, 95% confidence interval (CI) 0.95 to 1.79; 3 trials) or hepatic mortality (41/532 (7.7%) versus 40/552 (7.2%); RR 1.07, 95% CI 0.70 to 1.63; 2 trials); however, all-cause mortality was higher in the recipients of the pegylated interferon (78/828 (9.4%) versus 5 7/848 (6.7%); RR 1.41, 95% CI 1.02 to 1.96) when only the two low risk of bias trials were considered. The excess deaths appeared to be from non-liver causes. Variceal bleeding occurred less often in the treated patients (4/843 (0.5%) versus 18/867 (2.1%); RR 0.24, 95% CI 0.09 to 0.67), but there were no differences seen with regard to the subsequent development of other manifestations of end-stage liver disease (that is, encephalopathy, ascites, hepatocellular carcinoma, liver transplantation). One trial reported quality of life data; the treated patients had increases in their pain scores. No cost data were available. The recipients of the pegylated interferon generally had more adverse events; statistically significant differences were seen for the occurrence of hematologic complications, infections, flu-like symptoms, and rashes. Those receiving interferon were more likely to have sustained viral responses (20/557 (3.6%) versus 1/579 (0.2%); RR 15.38, 95% CI 2.93 to 80.71) and were also more likely to have improvements in markers of inflammation. No difference was demonstrated regarding the effect of the treatment on markers of fibrosis. The use of longer-term (several years) interferon monotherapy in patients with severe underlying hepatic fibrosis who have failed previous courses of treatment is not supported by the evidence; no trials providing data regarding clinical outcomes were identified in other potential treatment scenarios. Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated.