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Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)‐naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA‐naïve CHB patients, particularly in those with detectable hepatitis B virus (HBV) DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multicenter cohort study, we investigated 333 CHB patients treated with entecavir monotherapy. The NA‐naïve population consisted of 243 patients, whereas 90 were NA‐experienced. Virological response (VR) (HBV DNA <80 IU/mL) was achieved in 48%, 76%, and 90% of hepatitis B e antigen (HBeAg)‐positive and in 89%, 98%, and 99% of HBeAg‐negative NA‐naïve patients at weeks 48, 96, and 144, respectively. Thirty‐six of 175 (21%) NA‐naïve patients with at least 48 weeks of follow‐up had a detectable load at week 48 …