OBJECTIVES:  This study aimed to evaluate the effect of antiviral therapy on patients’ health-related quality of life (HRQoL) in an observational clinical study of nucleos(t)ide analogue (NUC) treatment for chronic hepatitis B (CHB) in China. METHODS:  NUC naïve CHB patients were recruited from 63 hospitals across China. The HRQoL of the patients was assessed using the EQ-5D-3L questionnaire prior to initiation of NUC treatment and reassessed at 24, 48, 72, and 96 weeks after treatment initiation. Changes in ‘poor’ HRQoL status, defined as reporting any of the five EQ-5D health problems, and the EQ-VAS score were examined, with missing data imputed using the last-observation-carried-forward method. RESULTS:  Of 3438 patients (mean age: 39.5 years; female gender: 26.2%) enrolled, the majority was inpatient (53.6%) and treated with entecavir (53.1%). The proportion of patients (95% confidence interval [CI]) in poor HRQoL monotonically decreased from 24.9% (23.4% to 26.3%) before treatment to 18.1% (16.8% to 19.3%) at 24 weeks, 16.6% (15.4% to 17.9%) at 48 weeks, 15.1% (13.9% to 16.3%) at 72 weeks, and 14.3% (13.1% to 15.4%) at 96 weeks after treatment initiation. The mean EQ-VAS score (95%CI) increased from 83.3 (82.9 to 83.8) before treatment to 86.5 (86.1 to 86.9) at 24 weeks, 86.9 (86.5 to 87.4) at 48 weeks, 87.4 (86.9 to 87.8) at 72 weeks, and 87.9 (87.5 to 88.3) at 96 weeks after treatment initiation. Among 854 patients who were in poor HRQoL before treatment, only 33.6% remained in poor HRQoL at 96 weeks after treatment; the mean EQ-VAS score (95%CI) increased from 75.3 (74.3 to 76.3) before treatment to 84.2 (83.3 to 85.2) at 96 weeks after treatment. CONCLUSIONS:  The HRQoL of CHB patients in mainland China continuously improves in their first two years of antiviral therapy. The treatment effect is more salient among patients in poor health.