We have previously demonstrated that combination peginterferon and lamivudine treatment has superior antiviral efficacy to lamivudine monotherapy in chronic hepatitis B. In this study, we investigated the long-term posttreatment virological response to this combination treatment. Sustained virological response of patients who completed 32-week peginterferon and 52-week lamivudine combination treatment was compared to patients who completed 52-week lamivudine monotherapy. Sustained response was defined as sustained hepatitis B e antigen (HBeAg) loss and HBV DNA < 100,000 copies/mL from treatment cessation until the end of follow-up. Forty-eight patients receiving combination treatment and 47 patients receiving lamivudine monotherapy were studied. The posttreatment follow-up of patients who received combination treatment was 117 ± 34 weeks and that of patients receiving lamivudine monotherapy was 124 ± 29 weeks. At the end of treatment, HBeAg loss occurred in 63% of patients in the combination group and 28% of patients in the lamivudine group (P = .001). The probabilities of sustained response for combination treatment and lamivudine monotherapy were 33% and 13% at week 24, 31% and 11% at week 52, and 29% and 9% at week 76, respectively (log-rank test, P = .0015). No patients developed virological relapse after week 76 until the last visit in either treatment group. All sustained responders had no biochemical relapse (alanine aminotransferase [ALT] > 2 times upper limit of normal) during follow-up. Among the non-sustained responders, biochemical relapse occurred in 32 patients (94%) in the combination group and 38 patients (88%) in the lamivudine group, respectively. In conclusion, combination treatment of peginterferon and lamivudine has a higher sustained virological response than lamivudine monotherapy up to 3 years after treatment. (HEPATOLOGY 2005.)