Background/Aims To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naïve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. Methods This study enrolled 73 antiviral-naïve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. Results During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naïve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). Conclusion The long-term clinical outcomes of antiviral-naïve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression.