The treatment of chronic hepatitis B (CHB) patients is based on monotherapy with pegylated‐interferon (Peg‐IFN) or with one of the three most potent nucleot(s)ide analogues (NUCs) with the best resistance profiles, i.e. entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Long‐term NUCs treatment can achieve virological suppression in almost all patients. However, this requires lifelong therapy, is costly and the rate of hepatitis B surface antigen (HBsAg) seroclearance is low. A one‐year course of Peg‐IFN has the advantage of providing immune‐mediated control of the hepatitis B virus (HBV) infection, the possibility of achieving a sustained off‐treatment response in nearly 30% of the patients and ultimately, HBsAg loss in approximately 30%‐50% of the latter patients during long‐term off treatment follow‐up. However, the major limitations to the extensive use of this treatment are the need for parenteral therapy and clinical and laboratory monitoring, the side‐effects profile and contraindications in certain patients and the limited effectiveness in a large proportion of patients. Nevertheless, the cost‐effectiveness of Peg‐IFN can be significantly increased by careful patient selection based upon baseline alanine aminotransferase (ALT), HBV DNA levels, viral genotype, host genetic variants and especially by applying early on‐treatment stopping rules based upon HBsAg kinetics. Recently, because of the different mechanisms of action of Peg‐IFN and NUCs, the strategy of “adding‐on” or “switching to” Peg‐IFN in patients being treated with NUCs to accelerate the decline in HBsAg and enhance HBsAg seroclearance rates, has provided interesting results.