The prognosis of patients with chronic hepatitis C after interferon (IFN) therapy is still poorly defined. The present study evaluated the effect of IFN therapy on survival in a cohort of such patients. The study included 459 patients with biopsy-proven C-viral chronic liver disease who were followed for 8.2 ± 2.9 years (range, 7-183 months). Survival status was examined by medical records or direct questionnaires. Fifteen (14%) of 104 IFN-untreated patients and 33 (9%) of 355 patients treated with IFN died during follow-up. Among the treated patients, 4 (3%) of 116 with sustained virologic response and 29 (12%) of 239 without sustained virologic response died. Liver-related death was shown in 32 (67%) patients, and hepatocellular carcinoma (HCC) caused 25 (52%) of the 48 deaths. Multivariate Cox proportional regression analysis revealed that IFN treatment decreased the risk ratio for overall death to 0.521 (confidence interval [CI]: 0.263-1.034) and for liver-related death to 0.208 (CI: 0.088-0.495) compared with untreated patients, and sustained virologic response showed a decrease in the risk ratio for overall death to 0.219 (CI: 0.068-0.710) and for liver-related death to 0.030 (CI: 0.003-0.267). IFN treatment showed no association with liver-unrelated death. Furthermore, the standardized mortality ratios for all causes of death and liver-related death were reduced in IFN-treated patients compared with untreated patients (1.4 vs. 2.0 for total death and 7.9 vs. 19.7 for liver-related death). In conclusion, the present data suggest that IFN therapy has a long-term clinical benefit for patients with chronic hepatitis C patients by reducing liver-related death, especially in patients with sustained virologic response.