Summary Background A short‐term course of pegylated‐interferon (Peg‐IFN), or a long‐term treatment with a third generation nucleot(s)ide analogue (NUC), of chronic hepatitis B (CHB) infection achieves viral suppression and may prevent disease progression. Owing to different mechanisms of action of the two regimens, a Peg‐IFN and NUC combination treatment may be an attractive approach to enhance the off‐treatment rates of virological and serological response. Aim To review the literature on combinations of Peg‐IFN plus NUC, including the simultaneous initiation of Peg‐IFN and NUC in naïve patients; an ‘add‐on’ combination, where Peg‐IFN is started at variable times after the beginning of NUC; or a ‘switch‐to’ strategy usually from NUC to Peg‐IFN. Methods We performed a PubMed literature search using the following terms individually or in combination: NUC, hepatitis B virus, chronic hepatitis, interferon, pegylated‐interferon, nucleos(t)ide analogues, entecavir, tenofovir. English‐language articles published up to December 2015, as well as conference proceedings from international meetings were reviewed. References from selected papers were reviewed and used if relevant. Results While combination and NUC pre‐treatment failed to increase HBsAg clearance rates, more promising results were achieved in patients under long‐term effective NUC therapy. Conclusion While Peg‐IFN and nucleos(t)ide analogue combination therapy should not be recommended currently, the addition of or the switch to Peg‐IFN in nucleos(t)ide analogue‐treated patients with chronic hepatitis B infection may be useful option.