This article discusses the clinical value of Pegylated Interferon (PEG-IFN) α-2a combined with entecavir or tenofovir in the treatment of Chronic Hepatitis B (CHB) genotype C patients. 78 patients with CHB genotype C were divided into three groups: control group, entecavir group, and tenofovir group according to different treatment methods. The efficacy and adverse reaction (AR) of the three groups are observed during 12 months of treatment and after drug withdrawal, and the clinical efficacy and safety of the three treatment methods are evaluated. The experimental results show that the sustained response rate (RR) in the tenofovir and entecavir groups is higher than that in the controls. The incidence of total AR in the tenofovir group is significantly higher than that in the control and entecavir groups. PEG-IFN α-2a and entecavir or tenofovir are more effective, and tenofovir has an antiviral effect.