Summary. Development of therapeutic strategies for patients with chronic hepatitis C who experience virological breakthrough, relapse or nonresponse lag behind those for treatment-naïve patients. The probability of a previously treated patient responding to re-treatment depends on the nature of the previous regimen, the magnitude of the response to previous treatment and the patient’s characteristics. Relapsers have higher sustained virological response rates than nonresponders when re-treated with pegylated interferon plus ribavirin. Re-treatment of nonresponders to pegylated interferon plus ribavirin with the standard 48-week regimen resulted in an approximate 6% sustained response rate in the EPIC-3 program. In the REPEAT trial, the sustained response rate was significantly higher in nonresponders to pegylated interferon alfa-2b (12 kD) plus ribavirin randomized to 72 weeks of peginterferon alfa-2a (40 kD) plus ribavirin, compared with a 48-week regimen (16%vs 8%, P = 0.0006). Based on available data, extended treatment is the best option for these individuals. Undetectable viral RNA at week 12 is an important criterion for re-treatment in the REPEAT and EPIC studies. Maintenance therapy with pegylated interferon is generally ineffective in nonresponders and cannot be recommended. Directly acting antivirals may increase response rates and the burden of adverse events when combined with the standard of care, but will not be available for some years. In conclusion, after careful evaluation of an individual’s benefit–risk ratio, a 72-week regimen is the preferred strategy for optimizing sustained response rates in patients who have not responded to the standard of care, provided that viral RNA is undetectable at week 12 of re-treatment.