Chronic hepatitis B infection (CHB) causes up to 1.0 million deaths annually. Currently, more than 90% of CHB patients worldwide are receiving indefinite nucleos(t) ide analogue (NA) therapy. New strategies for optimizing hepatitis B surface antigen (HBsAg) loss are required for NA-treated patients as the majority are unable to achieve HBsAg loss and may require lifelong therapy. In hepatitis B e antigen (HBeAg)-positive patients, switching from NAs to finite peginterferon (PegIFN) therapy can double HBeAg seroconversion rates. One in five patients who switch to PegIFN can achieve HBsAg loss, whereas patients who continue NA therapy typically do not. In HBeAg-negative NA-treated patients, add-on PegIFN therapy achieves higher, albeit modest, HBsAg loss rates compared with continued NA monotherapy and offers the opportunity for NA-treated patients to achieve the inactive carrier state. In the absence of curative therapies, PegIFN represents a valuable, finite option for NA-treated patients who would otherwise require potentially lifelong therapy.