Entecavir treatment failure can be observed in compliant patients despite an absence of detectable resistance mutations by Pol/RT Sanger sequencing. We hypothesized that these unexplained treatment failures could rely on other mechanisms of viral resistance, especially on mutations selected outside of the Pol/RT domain. Partial virological response to entecavir was observed in three patients treated with immunosuppressive drugs, without selection of Pol/RT resistance mutations. Mutations selected in the whole HBV genome during entecavir treatment and potentially associated with resistance were searched for using deep sequencing and characterized using a phenotypic resistance assay. Mutations Q206K (pre-core/core), Q120K (pre-S1/pre-S2, T-cell epitope) and A300E (spacer domain) were selected during entecavir treatment in patient #1 but were not associated with an increased level of resistance to entecavir or an increase in HBV replication capacity. Core promoter mutations T1753G, A1762T and G1764A were present before treatment in patient #1. HBs Ag immune escape mutations were present before treatment in patients #2 (sK122R, sT126I, sP127S and sG145R) and #3 (sM133I). These results provided a unique insight into the evolution of HBV quasispecies during entecavir treatment, addressing the whole HBV genome and not only the Pol/RT domain. Our results suggest that mutations selected outside of the Pol/RT domain could contribute to entecavir treatment failure, not by an increased level of resistance, but by an immune escape mechanism, in synergy with immunosuppressive drugs.