Patients with chronic hepatitis B (CHB) with low hepatitis B surface antigen (HBsAg) levels and suppressed hepatitis B virus (HBV) DNA on nucleos(t)ide analogues (NAs) may achieve functional cure with peginterferon α (PegIFNα)-based therapy. This real-world multicenter study (Everest Project) in China aimed to evaluate the effectiveness and safety of PegIFNα-2b and determine the predictors of HBsAg loss.Patients with NA-suppressed CHB who were hepatitis B e antigen (HBeAg)-negative, had HBsAg ≤1500 IU/mL, and undetectable HBV DNA, were administered PegIFNα-2b for 48 weeks, either as a switch-to or add-on therapy. The primary endpoint was HBsAg loss at week 48.Among 15,896 patients in the full analysis set (FAS) and 12,260 in the per-protocol set (PPS), HBsAg loss rate at week 48 was 26.4% and 33.8%, respectively, after propensity score weighting, with no significant difference between switch-to and add-on groups. Key predictors of HBsAg loss included lower baseline HBsAg and HBsAg decline >63.3% at week 12 and >95.3% at week 24. Among patients who underwent >24 weeks of post-treatment follow-up, HBsAg loss rates at week 24 were 28.7% and 35.6% in the FAS and PPS, respectively. Of those who received consolidation therapy, 85.9% maintained HBsAg loss at week 72. Adverse event-related discontinuation occurred in 5.6% and 4.4% of those in the FAS and PPS, respectively.PegIFNα-2b enhances HBsAg loss in patients with NA-suppressed, HBeAg-negative CHB with low HBsAg levels. Baseline and on-treatment predictors support the achievement of a functional cure.gov, Number: NCT04035837.