The aim of this study was to compare the long-term efficacy of entecavir (ETV) and lamivudine (LAM) therapy in children with chronic hepatitis B (CHB) who had not received nucleoside analogue. In this multicenter, retrospective study, we included pediatric CHB patients who received ETV or LAM treatment at least 12 months (mo.) below 20 years old and had no concomitant disease. All of the patients were visited every 1 to 3 months, at every visit, clinical evaluation, biochemical test were checked. Eight (53.3%), 14 (93.3%) and 2 (15.4%) of the ETV treated patients achieved virologic suppression, ALT normalization and HBeAg seroconversion at 1 year. In ETV group, the cumulative rate of virologic suppression at 3 year was 91.7% significantly higher than LAM group (p0.001). The mean duration of treatment to virologic suppression was rapid in ETV group than LAM group (p=0.04). The cumulative rate of seroconversion of ETV at 3 years was 39.4% which was not significantly different from LAM (p=0.439). The ETV group revealed lower cumulate rate of virologic breakthrough and genotypic mutation than LAM group (p=0.033, p=0.011). In conclusion, entecavir is superior to lamivudine in pediatric CHB treatment for higher virologic suppression rate, and lower cumulative rate of virologic breakthrough and genotypic mutation.