Background: Hepatitis B virus infection (HBV) is one of the major public health problems, which in addition to physical disorders, affects patients' quality of life (QoL). In Egypt, the prevalence of HBV is 1% while 87.2% of the liver cirrhosis patients reported poor QoL. Objective(s): The present study was conducted to investigate the effect of chronic hepatitis B (CHB) on the QoL in Egypt. Methods: An observational cross-sectional study was conducted in the Clinic of “On State Expenses Treatment" in Alexandria and Cairo for 18 months using WHOQO-BREF 26 questionnaire. It is composed of four domains: physical, social, psychological, and environmental. Each domain included different facets. A total of 294 HBV patients, as well as 64 physicians, as a control, participated in the study. Representation of the different chronic hepatitis B clinical stages was ensured. Results: The overall 100-format QoL score was low (0.2). The QoL score among Hepatocellular Carcinoma (HCC) patients was the lowest, with the physical domain being greatly impaired, while the QoL score in the Chronic hepatitis B clinical stage was the highest, with the psychological domain showing the greatest impairment. Stepwise multiple regression modeling resulted in three main predictors (classification of the clinical stage, marital status, and smoking). These predictors were responsible for 41% of the variance in the QoL score. The classification of the clinical stage and smoking were inversely correlated to the QoL, the marital status was positively correlated. Conclusion: The current study highlighted the importance of social support in the management of CHB patients. Moreover, the rehabilitation programs in the late stages of the disease are highly recommended, as the physical aspects become more affected at the end stage of the disease, as well as psychological aspects. The importance of early diagnosis and management of cases is an important priority especially with the fact that the clinical stage is a major predictor of the overall QoL of the patients.