Objective To investigate the efficacy and safety of Tenofovir Alafenamide Fumarate combined with Pegylated Interferon α-2b in the treatment of patients with chronic hepatitis B. Methods A total of 82 patients with chronic hepatitis B who were treated in Sihong County People's Hospital from May 2018 to May 2020 were selected as the study subjects and divided into study group (n=41) and control group (n=41) according to random number table method.The control group was treated with Tenofovir Alafenamide Fumarate, and the research group was treated with Pegylated Interferon α-2b on the basis of the control group.The clinical efficacy and medication safety of the two groups were compared. Results After 12 months of treatment, the hepatitis B virus DNA (HBV-DNA) in the study group was lower than that in the control group, and the difference was statistically significant (P＜0.05).The normalization rate of alanine aminotransferase (ALT) in the study group was higher than that in the control group after 6 and 12 months of treatment,and the differences were statistically significant (P＜0.05).The serum conversion rate of hepatitis B e antigen (HBeAg)in the study group was higher than that in the control group after 6 months of treatment, and the serum conversion rate of HBeAg and HBeAg in the study group were higher than that in the control group after 12 months of treatment, and the differences were statistically significant (P＜0.05).There was no significant difference in the total incidence of adverse reactions between two groups (P＞0.05). Conclusion Tenofovir Alafenamide Fumarate combined with Pegylated Interferon α-2b in the treatment of chronic hepatitis B patients has good clinical efficacy, and the incidence of adverse reactions in patients is less, and the drug safety is high.