Background <p>Soluble PD-1 (sPD-1) has emerged as a potential biomarker in chronic hepatitis B (CHB), but its predictive value for treatment response remains unclear.</p> Objective <p>To examine the relationship between sPD-1 dynamics and HBsAg loss in HBeAg-negative CHB patients undergoing IFN-based therapy and assess the potential of sPD-1 as a biomarker for treatment response.</p> Methods <p>We enrolled 222 HBeAg-negative CHB patients from a prospective study. Patients received at least 48 weeks of PEG-IFNα-2b therapy and were grouped based on HBsAg status at week 48 (loss vs. persistence). Peripheral blood sPD-1 levels were measured by ELISA, and PD-1 expression on CD4⁺ and CD8⁺ T cells was analyzed by flow cytometry. Propensity score matching (PSM) and Cox regression were applied to identify predictors of HBsAg loss.</p> Results <p>Among the patients, 38.7% (86/222) achieved HBsAg loss. After PSM, both the HBsAg loss and HBsAg persistence groups included 74 patients, respectively. A reduction in HBsAg of more than 70% at week 12 (<i>p</i> = 0.012) and baseline sPD-1 level lower than 100 pg/mL (<i>p</i> = 0.016) were identified as independent predictors of HBsAg loss. sPD-1 levels showed a positive correlation with HBsAg levels, whereas PD-1 expression on peripheral CD4⁺ and CD8⁺ T cells demonstrated no significant association with HBsAg levels, suggesting that sPD-1 may better reflect systemic immune status.</p> Conclusions <p>sPD-1 may serve as a potential biomarker for predicting HBsAg loss in HBeAg-negative CHB patients undergoing IFN-based therapy.</p> Graphical abstract <p></p>