The aim of this study was to assess the long term impact of ETV on T, B and NK cell immunity in patients with suboptimal responses to adefovir (SRA) chronic hepatitis B (CHB). Thirty SAR CHB patients and 20 age‐/gender‐matched healthy controls (HC) completed at least six months of ETV treatment. HBV DNA loads, ALT and AST, and the frequency of different subsets of T, B and NK cells in individual subjects were measured. There were smaller numbers of CD3‐CD56+ and CD244+ NK cells, CD3+CD8+ T cells, and cytokine‐secreting CD4+T cells, but greater numbers of CD3+CD4+, CD4+CD25+Foxp3+, CD4+CD25+CD127low T cells and CD19+CD27+ B cells detected in SRA patients. After switching to ETV monotherapy, the levels of HBV DNA and HBsAg, as well as HBeAg seropositivity gradually decreased, accompanied by decreased levels of ALT and AST. Furthermore, the numbers of NK, CD8+ and cytokine‐secreting CD4+ T cells were increased, but CD4+, CD4+CD25+Foxp3+, CD4+CD25+CD127low T cells and CD19+CD27+ B cells in SRA CHB patients were decreased. The frequency of CD4+IFNγ+ T cells were negatively associated with serum HBV DNA levels. Thus, treatment with ETV inhibits HBV replication, modulates T and NK cell immunity and improves the liver function in SAR CHB patients. This article is protected by copyright. All rights reserved.