Abstract: Objective To investigate the effect of pegylated interferonα-2a ( PEG-IFN α-2a) combined with thymosin α1 ( Tα1) on the quality of life ( QOL) in patients with chronic hepatitis B ( CHB) . Methods A total of 148 patients with CHB who were admitted to our department from October 2008 to October 2012 were selected and randomly divided into observation group ( n = 74) and control group ( n =74) . The control group was treated with PEG-IFN α-2a, while the observation group was treated with PEG-IFN α-2a plus Tα1. The hepatitis B virus ( HBV) DNA load, QOL, Chronic Liver Disease Questionnaire scores, and adverse reactions were compared between the two groups at months 3, 6, and 12 of treatment. Comparisons between groups were made by independent-samples t test; comparisons between variables before and after treatment were made by paired t test; categorical data were analyzed by chi-square test. Results Compared with the control group, the observation group had significantly higher decrease in HBV DNA load and virological response rate at months 3 ( t = 2. 281, P = 0. 02; χ2= 3. 950, P = 0. 04) , 6 ( t = 3. 237, P = 0. 00; χ2= 4. 022, P = 0. 04) , and 12 ( t = 3. 197, P = 0. 00;χ2= 4. 028, P = 0. 04) , significantly higher overall QOL, physiological, social relation, fatigue, and anxiety scores at month 6 ( t = 2. 039-3. 472, P < 0. 05) , and significantly higher overall QOL, general health status, physiological, psychological, social relation, fatigue, systemic symptom, activity, anxiety, and environment scores at month 12 ( t = 2. 020-3. 201, P < 0. 05) . Conclusion PEG-IFN α-2a combined with Tα1 can improve immunity and antiviral ability and promote HBV clearance in the treatment of CHB, thus leading to the improvement in patients' QOL. This therapy holds promise for clinical application.