Introduction: Health-related quality of life (HRQoL) has emerged as an important consideration in the care of patients with chronic hepatitis B (CHB). However, whether benefits from the improved HRQoL that occurs after antiviral treatment or drug discontinuation outweigh the risks of viral relapse is an unanswered question. The aim of this study was to evaluate the HRQoL among patients with CHB during antiviral treatment and withdrawal of treatment. Patients and methods: There were 102 patients who met the enrollment criteria with 54 patients in the treatment group and 48 patients in the discontinuation group. Sociodemographic information was collected. The 36-Item Short-Form Health Survey (SF-36), European Quality of Life-5 Dimensions, and Beck Depression Inventory (BDI) were adopted to evaluate life quality and mental health. Results: In the treatment group, SF-36 showed that the physical functions were significantly increased. In the discontination group, the psychological functions showed improvement. A multivariate regression analysis indicated that baseline SF-36 score was a predictor for improvement in HRQoL (odds ratio = 1.17, P=0.003) and baseline BDI score was a factor for remission of depression (odds ratio = 0.75, P=0.005) after medical intervention. When the cutoff value of SF-36 score was set at 79.5, the sensitivity and specificity to predict improvement in HRQoL were 82.8% and 74.0%, respectively. When the cutoff value of BDI was found as 8.5, the sensitivity and specificity to predict alleviation of depression were 58.6%, and 76.0%, respectively. Conclusion: Antiviral treatment benefits the physical health of the patients with CHB, while conferring no obvious improvement in their psychological condition. Improved psychological interventions for patients with CHB, especially for those with lower baseline SF-36 scores and higher BDI scores, may improve their quality of life.