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Background Quantitative hepatitis B surface antigen (qHBsAg) is an important biomarker in chronic hepatitis B (CHB).Objective Establish qHBsAg profiles to guide novel drug development.Design Baseline qHBsAg profiles, longitudinal qHBsAg trajectories and predictors of HBsAg seroclearance were determined in a large CHB cohort.Results This study included 4287 patients with qHBsAg measurements between 2009 and 2020 (62.5% male; mean age 48.0; 45.2% on nucleos(t)ide analogues (NUC)) with median baseline qHBsAg of 630.8 (117.1–1875.5) IU/mL. 3437 (80.2%), 2516 (58.7%) and 997 (23.3%) patients had baseline qHBsAg <3000 IU/mL, <1000 IU/mL and <100 IU/mL, respectively (69.2%, 46.9% and 22.9% in treatment-naïve; 93.4%, 73.0% and 23.6% in NUC-treated patients correspondingly). Among patients with recent qHBsAg measurements in 2018 (n=1593), 98.9%, 71.1% and 26.9% of patients had baseline qHBsAg <3000 IU/mL, <1000 IU/mL and <100 IU/mL, respectively (99.3%, 67.1% and 34.2% in treatment-naïve; 98.7%, 73.1% and 23.0% in NUC-treated patients correspondingly). Age (OR 1.019–1.049), hepatitis B e antigen positivity (OR 0.264–0.349) and HBV DNA (OR 0.675–0.832) were independent determinants of qHBsAg <100 or 1000 IU/mL, respectively (all p<0.05). Among patients with serial qHBsAg measurements, the median qHBsAg reduction was 0.10 (0.02–0.27) log IU/mL/year. After median follow-up for 6.3 (5.7–14.3) years, 526 patients (12.3%) achieved HBsAg seroclearance. Baseline alanine aminotransferase/qHBsAg ratio ≥0.27 independently predicted HBsAg seroclearance (HR 4.904, p<0.001).Conclusion In an endemic population, >40% of patients with CHB have qHBsAg >1000 IU/mL. These patients are unlikely to achieve spontaneous HBsAg seroclearance, but also have suboptimal responses to novel antivirals. Our data has important implications for novel antiviral development.