Bepirovirsen, an antisense oligonucleotide, induces sustained hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA below lower limit of quantification (<LLOQ) in a subset of patients. The B-Together study investigated if sequential bepirovirsen and pegylated interferon-α-2a (Peg-IFN) therapy can reduce relapse and improve response rates. Phase 2b, multicentre, randomised, open-label trial. Participants on stable nucleos(t)ide analog (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 mcg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. proportion of participants with HBsAg <0.05 IU/mL and HBV DNA <LLOQ for 24 weeks after planned end of Peg-IFN treatment, in the absence of newly initiated antiviral therapy. The intent-to-treat population included 108 participants (Arm 1=55; Arm 2=53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3000 IU/mL. Indirect comparison with the Phase 2b study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events (AEs) and treatment-related AEs in both treatment windows were similar between treatment arms. Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse. GSK (study 209348/NCT04676724). NCT04676724.