Objective To investigate the clinical effect of traditional Chinese medicine syndrome differentiation-based treatment combined with entecavir in the treatment of chronic hepatitis B. Methods A total of 80 outpatients with chronic hepatitis B were randomly divided into the observation group (n=40) and control group (n=40).The patients in the control group were treated with entecavir tablets. The patients in the observation group were given TCM syndrome differentiation-based treatment in addition to the treatment received by the control group. Clinical symptoms relief, improvement of liver function indexes, serological conversion and HBV-DNA negative rate were compared between the two groups after 48 weeks of treatment. Results The clinical symptoms of abdominal distension, fatigue, pain and anorexia were relieved better in observation group than in control groups. The difference was significant between the two groups (P<0.05). The observation group had significant therapeutic advantages over the ALT recurrence rate compared to the control group, especially 24 weeks ago (P<0.05). There was no statistically significant difference between the combined group and the control group after 12, 24, 48 weeks after treatment, and the HBV-DNA (both greater than 0.05) were clinically modified. Conclusion TCM syndrome differentiation-based treatment combined with entecavir had significant therapeutic advantages in the treatment of chronic hepatitis B, which could relieve clinical symptoms, improve liver function indexes, and converse serological changes and be worthy of clinical popularization.