Background/Aims We investigated the efficacy of entecavir in lamivudine-experienced and -naïve patients with persistently high HBV DNA during adefovir treatment. Methods Fourteen chronic hepatitis B patients (57% lamivudine-experienced) with a viral load above 5 log 10 copies/mL after 12 months of adefovir therapy and thereafter were treated with entecavir 1 mg daily. Results During a median follow-up of 15 months (range: 8–23 months) one of six lamivudine–naïve and none of the eight lamivudine-experienced patients achieved undetectable HBV DNA (<373 copies/mL). HBeAg loss occurred in none of the subjects. Two lamivudine-experienced patients demonstrated the rtM204I mutation; no other entecavir-resistant substitutions were detected (rtI169, rtT184, rtS202, and rtM250). Two of three patients with genotypic adefovir resistance at baseline demonstrated a rapid virologic response to entecavir, but undetectable HBV DNA was not achieved. To attain a better antiviral response the dosage of entecavir was increased to 2 mg daily in two patients, resulting in further viral load decline for both of them. Conclusions Entecavir monotherapy dosed at 1 mg resulted in a slow reduction of viral load in both lamivudine-experienced and -naïve patients with persistently high HBV DNA during adefovir therapy. Increasing the dosage of entecavir led to further HBV DNA decline.