To observe the clinical efficacy of Huaier granule combined with interventional treatment on patients with HBV DNA-negative Hepatitis B and record the adverse reaction. Methods:A total of 120 liver cancer patients with HBV DNA-negative Hepatitis B were randomly divided into intervene group and control group, with 60 patients in each group. Control group received intervention, percutaneous puncture of femoral artery, then injected Pirarubicin hydrochloride for injection + lipiodol in parent artery until blood stagnation + antivirus (entecavir), and also conventional liver protection therapy was conducted; intervene group additionally received Huaier granule for continuous 6 months. Clinical efficacy, HBV DNA quantification, and liver function indexes in the two groups were compared. Results:After treatment, short and long-term clinical efficacy in observation group was significantly better than the control group (P<0.05). Before the treatment, there were no significant differences in HBV DNA quantification and liver function (P>0.05). After treatment, the HBV DNA quantification and liver function were both lower than before treatment in both groups (P<0.05), and the HBV DNA quantification and liver function were lower in the intervene group than control group (P<0.05). After treatment, the cell-mediated immunity and humoral immunity were both better than before treatment in both groups (P<0.05), and the cell-mediated immunity and humoral immunity were better in the intervene group than control group (P<0.05). During the treatment, reducing leucocyte and platelet, nausea, vomit, etc. were occuring in both groups. Conclusion:Huaier granule combined with interventional treatment on patients with HBV DNA-negative Hepatitis B can improve the clinical efficacy, with less side effects.