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We studied whether 48 weeks of PEG‐IFN alfa‐2a add‐on increases HBsAg‐decline and clearance in HBeAg‐negative patients on long‐term nucleo(s)tide analogue (NA) therapy. In this investigator‐initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg‐negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG‐IFN alfa‐2a add‐on (180 μg per week) or continued NA‐monotherapy with subsequent follow‐up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified‐intention‐to‐treat analysis, 58 patients received PEG‐IFN add‐on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add‐on arm versus none on NA‐monotherapy (p <.001), and HBsAg clearance was observed in 6 (10%) PEG‐IFN add‐on patients versus 0% NA‐monotherapy (p =.01). HBVRNA was only detected in 2% after PEG‐IFN treatment versus 19% in NA‐monotherapy (p =.002) at Week 48. PEG‐IFN add‐on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG‐IFN add‐on, whereas an HBsAg level > 200 IU/mL at on‐treatment Week 12 was highly predictive of non‐response (NPV = 100%). Addition of PEG‐IFN to long‐term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg‐negative patients on long‐term NA. On‐treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG‐IFN add‐on and could be used as a potential stopping‐rule for PEG‐IFN therapy. Our findings support further exploration of immune modulation add‐on to antiviral therapy, preferably using response‐guided strategies, to increase functional cure rates in patients with CHB. [ABSTRACT FROM AUTHOR]